Bioaccessibility and Bioavailability of Phenolic Compounds

Journal of International Society for Food Bioactives Nutraceuticals and Functional Foods

Review J. Food Bioact. 2018;4:11–68

Bioaccessibility and bioavailability of phenolic compounds

Fereidoon Shahidi* and Han Peng

Department of Biochemistry, Memorial University of Newfoundland, St. John’s NL, Canada A1B 3X9 *Corresponding author: Fereidoon Shahidi, Department of Biochemistry, Memorial University of Newfoundland, St. John’s NL, Canada A1B 3X9. Tel: 709 864 8552; Fax: 709 864 2422; E-mail: [email protected] DOI: 10.31665/JFB.2018.4162 Received: October 8, 2018; Revised received & accepted: November 7, 2018 Citation: Shahidi, F., and Peng, H. (2018). Bioaccessibility and bioavailability of phenolic compounds. J. Food Bioact. 4: 11–68.

Abstract

Modern epidemiological and interventional studies have demonstrated that various bioactivities including antioxidant, antiproliferative, immune-regulatory, hormonal-regulation abilities and neuro-/hepato-/cardioprotective effects result from consumption of a phenolic-rich diet. The health benefits of ingesting phenolics are greatly dependent on their bioaccessibility and bioavailability in the digestive tract and circulatory system. This contribution attempts to review the bioaccessibility and bioavailability of phenolic compounds by focusing on the body’s internal mechanism including digestion, absorption, transport, modification, excretion, and colonic fermentation. The bioaccessibility and bioavailability of different phenolics vary depending on the physical condition of an individual, including digestive/absorptive/metabolic/response capability and effective dose. External factors such as processing methods and interaction with various food matrices also play a vital role on the bioavailability of dietary phenolic compounds. On the other hand, some novel phenolics have been synthesized to enable them rendering new bioactivities. The key internal factors influencing the bioaccessibility and bioavailability are also reviewed in this contribution. In addition, suggestions have been made for future measurement and assessment of bioavailability, together with prospects for food/nutraceutical/pharmaceutical application of novel phenolics.

Keywords: Phenolics; Bioavailability; Transporters; In vivo metabolism; Colonic catabolism.

1. Introduction effective dose. Besides common phenolics that serve as antioxidants, some novel phenolic compounds have been discovered, syn- Dietary phenolic compounds constitute one of the most important thesized or modified to reveal new properties as well as enhancing groups of natural antioxidants and chemopreventive agents. They their original bioactivities such as antioxidant, antimicrobial, an- include phenolic acids, flavonoids, stilbenes, coumarins, lignans, tiproliferative, immune-regulatory, hormonal-regulation abilities lignins, and oligomeric and polymeric proanthocyanidins, among and neuro-/hepato-/cardioprotective effects (Maeda-Yamamoto et others. Numerous epidemiological and interventional studies have al., 2017; Patel, 2014; Peng et al., 2017). However, excessive ex- demonstrated that consumption of phenolic-rich foods is inversely posure to phenolics upon dietary ingestion and intravenous injec- associated with the risk of most common oxidative stress-associ- tion may also render adverse effects on health (Galati and O’brien, ated degenerative and chronic diseases, including cardiovascular 2004; Skibola and Smith, 2000; Watjen et al., 2005). In compari- disease (CVD), type-II diabetes mellitus, cancer and aging (Am- son, modified lipophilic phenolics, as well as the production of arowicz and Pegg, 2008; Villegas et al., 2008). A balanced diet small size nanoparticles, may exert toxicity at a lower dose while provides many different phenolic compounds and seasonal and few studies have so far been conducted to support such a hypoth- cultural dietary changes in every country result in their differential esis. Therefore, in considering phenolic compounds, it is impera- bioavailability. In addition, the bioaccessibility and bioavailabil- tive to remember both their nutraceutical potential and application ity of different phenolics vary depending on individuals’ physical limitation; it is also important to know the content of phenolics condition, including digestive/absorptive or metabolic ability and present in specific food or dietary supplement and their bioavail-

studies focusing on bioactivity assessment and in vitro cell pathway investigations are still in progress. The results so obtained are cell line-dependent. However, bioactivities of phenolics are compared and reported often not under similar in vitro conditions in different reports. Besides, bioactivity experiments conducted in vitro especially in cell line tests are also concentration-dependent, and the actual phenolic metabolites are not what they originally were, hence consideration of realistic concentrations and metabolites in action sites which is determined by bioaccessibility and bioavailability criteria is essential. On the other hand, different from common nutritional compounds, phenolics are also regarded as anti-nutrients and non- nutritive bioactive compounds. Normally, all foods we eat are composed of nutrients and/or non-nutrients. Food nutrients are mainly carbohydrates, proteins, lipids, vitamins, minerals, and water and serve as a source for energy production, tissue/organ construction, and co-factors in intermediary metabolisms, while non-nutrients could be indigestible polysaccharides, phytochemicals, medical ingredients, and several inactive substances that may be in charge of mechanism modulation, disease prevention/treatment, and various other biological functions (Kanazawa, 2011; Pan et al., 2018; Velderrain-Rodríguez et al., 2014). For both nutrients or non-nutrients, bioaccessibility and bioavailability could be regarded as bio-efficiency. Specifically, bioaccessibility is the digestion and absorption efficiency (or digestibility and absorptiv- Figure 1. Schematic representation of phenolic bioavailability. ity) of a certain food constituent or drug ingested by oral administration, normally expressed as a percentage of the actual amount ability. released and absorbed constituent to its total content. However, The health benefits of ingested phenolics greatly depend on their for bioavailability, there are significant differences between that of bioaccessibility and bioavailability in the digestive tract and circu- nutrients and non-nutriments. In the nutrition area, bioavailability latory system. Among different phenolics, bioavailability differs is crudely defined as the utilized or stored proportion of the total greatly, the ones with most abundance or highest in vitro activity in administered quantity. For non-nutrients, such as medicines, bio- the daily diet do not necessarily positively correlate to those with availability is more strictly defined. According to 21 CRF 314.3 the best bioaccessibility and bioavailability profile (Carbonell- (2016) of Food and Drug Administration (FDA), Code of Federal Capella et al., 2014). Several decisive steps, including the effects Regulations, bioavailability of drugs is defined as the available ra- of digestion rate, first passing effect, metabolic modification and tio of active ingredient or active moiety absorbed and detected in colonic fermentation have attracted much attention in order to the target site to the total amount of orally ingested drug products; investigate the generalized evaluation method of bioavailability the intravenously administrated medication is defined as having a for phenolics-dominated functional foods, nutraceuticals, dietary bioavailability of 100%. supplements, and drugs. The structural characteristics including Bioactive compounds or bioactives refer to substances that functional groups and polymerization enable phenolics to present have an effect on human health; this kind of compounds are dis- different solubilities and be absorbed and metabolized in their own tinguished from both nutrients and non-nutrients but overlapping pathway, therefore also resulting in a varied function of phenolics, with them at the same time (Biesalski et al., 2009). Their bioavail- compared to other phytochemicals. Meanwhile, external factors ability is partially overlapped with pharmacological and nutritional play a vital role in bioaccessibility and bioavailability of phenolics principle (21-CFR-314.3, 2016; Etcheverry et al., 2012; Heaney, upon ingestion. Both interaction with various food matrix compo- 2001; Srinivasan, 2001). As shown in Fig. 1, bioavailability covers nents and diverse processing methods significantly influence the the range of bioaccessibility, metabolism and physiological activ- actual bioaccessibility and bioavailability of ingested phenolics. ity (or simply called bioactivity) (Carbonell-Capella et al., 2014; This contribution summarizes digestion, absorption, metabolism, Etcheverry et al., 2012; Gutiérrez-Grijalva et al., 2016). circulation and excretion process, as well as biological function As a food component, phenolics are not fully released and the and potential application of natural and synthetic phenolics. released phenolics are poorly absorbed. Furthermore, the absorbed phenolic molecules cannot be completely transported to the action site in order to exert their bioactive effects. In this connection, their 1.1. Definition of bioaccessibility and bioavailability physicochemical properties including the degree of polymerization or glycosylation and molecular properties, polarity and interaction The chemical and physiological effects of natural bioactive com- status with nutrients, as well as individual physiological conditions ponents in food manufacturing and dietary evaluation, and even such as the expression of transport protein and status of tissues are in phytopharmacological studies are well recognized. Among important factors to consider. Regardless of the individual differ- functional ingredients, the effects of phenolics on human health ences, the investigation on bioaccessibility and its effects provide are undeniable, not only as nutraceuticals and additives but also valuable information for the selection of proper phenolic ingested as therapeutic agents (Ferreira et al., 2017). Most of the action dose and cooking/processing method of food (Carbonell-Capella mechanisms and related pharmacokinetic parameters that depend et al., 2014). In this contribution, based on the overlap between on phenolics uptake are still poorly demonstrated and clarified. drug and dietary phenolics, the bioavailability of phenolics in- Meanwhile, based on in vivo observational health effects, many volved is taken with consideration of all the pharmacokinetic steps

12 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds of digestion, absorption, deposition, distribution, metabolism, ex- U/mL, at pH 7, for 2 min (volume of sample to volume of cretion, and function. digestion fluid, 1:1) 2. Simulated gastric treatment with a final pepsin activity of 2,000 U/mL, at pH 2, for 2 h (volume of sample to volume 2. Bioaccessibility of phenolics of digestion fluid, 1:1) 3. Simulated intestinal treatment with pancreatin based on a fi- 2.1. Liberation and in vitro simulated digestion nal trypsin activity of 100 U/mL, at pH 7, for 6 h (volume of sample to volume of digestion fluid, 1:1). In addition to the most primary condition of enzymes and pH, As defined in the introduction section, bioaccessibility consists of some standardized principles such as bile extract concentration (10 digestibility and absorptivity. Digestion is the breakdown of large mM), simulated gastrointestinal movement, body temperature, and insoluble food molecules, assisted by various digestive enzymes dark anaerobic environment are also necessary. Besides, there are and pH change, into small soluble molecules. The phenolic-matrix some other non-standardized conditions including food particle interaction determines phenolic liberation. For dietary phenolics, size, gastrointestinal transit time, special enzymes and the addition they are generally classified as free, conjugated and insoluble- of some media compounds such as emulsifiers and electrolytes in bound phenolics (Madhujith and Shahidi, 2009). Free phenolics simulated digestion process that also need to be considered (Hur et are present as phenolic aglycones and conjugated phenolics gener- al., 2011; Minekus et al., 2014). ally occur as phenolic glycosides, most of which are readily re- Several results about in vitro release rate of phenolics have been leased in the digestive juice and absorbed as cell membrane bursts summarized in Tables 2 and 3. Chandrasekara and Shahidi (2012) and cytoplasm diffuses into digestive juice by the effects of me- conducted a three-stage digestion test of five millet grain samples chanical or chemical digestion. The insoluble-bound phenolics are and found gastric digestion was the major release stage for Pas- covalently bound to indigestible matrices such as polysaccharides palum scrobiculatum and Elusine coracana (more than 80% of (pectin, hemicellulose, cellulose, and arabinoxylan), rod-shaped total releasable phenolics), but for Setaria italic and Panicum mil- structural proteins and highly-polymerized phenolics (condensed iacium was intestinal digestion. Due to the relatively low effects tannin and lignin) (Acosta-Estrada et al., 2014; Shahidi and Ambi- of oral treatment in the entire digestion efficiency, the three-stage gaipalan, 2016). These phenolics are partially or very marginally digestion is sometimes simplified into two-stage without its con- released, few of them penetrate through the intestinal epithelium sideration, which is more used in simulated digestion of various and arrive into blood, leading to a low bioaccessibility in the up- vegetables, fruits, beverages and other foods (Bermúdez-Soto et per intestinal tract (Peng et al., 2017; Shahidi and Yeo, 2016). De- al., 2007; Bouayed et al., 2011; Chen et al., 2015; Faller et al., pending on the species and fractions of the plant, the proportion 2012; Toydemir et al., 2013; Vallejo et al., 2004). of bound phenolics varies from 20 to 90% (Acosta-Estrada et al., Some studies report that the intestine is mainly responsible for 2014). While only less than 10% of phenolics could get through the liberation of phenolics. The effect of digestion on phenolic small intestinal epithelium into circulation system and exert bio- content and antioxidant activity of 33 fruits, for phenolic release, activity at the target cell and tissue, the rest of the phenolics flow was investigated by Chen et al. (2015). Each stage, especially in- to colon with other unabsorbed residues. This part of phenolics testinal digestion, was found to increase the phenolic content in the may be metabolized and released via fermentation in the colon and digestion fluid.Yang et al. (2018) found that the in vitro digestion could then be absorbed and further metabolized (Shahidi and Yeo, treatment with bile salts was 5 times higher than the counterpart 2016). It is reported that only 2.6% of total released ferulic acids without bile salts in phenolic release. However, for antioxidant ac- in wheat could be released by gastric and small intestinal diges- tivity, it only increased during the gastric process and decreased tion, and over 95% ferulic acids were released during colonic fer- severely in the intestinal process (Chen et al., 2015). According mentation (Kroon et al., 1997). To understand phenolic digestion, to the study of Chandrasekara and Shahidi (2012) on grain, flavo- phenolic release process includes the gastrointestinal digestion noids are released upon intestinal digestion better than highly-po- and colonic fermentation, both of which need to be emphasized. lar phenolic acids; this may be attributed to the longer release time Presently, various in vitro/in vivo methods including simulated and emulsification effect of intestinal digestion that is indispensa- gastrointestinal digestion, simulated colon fermentation, artificial/ ble for relatively hydrophobic flavonoids. Furthermore, comparing cultured/isolated semipermeable membrane system, Ussing cham- the control group without pH variation and enzyme treatment, the bers, animal intestinal perfusion, and animal/human pharmacoki- counterpart with only pH variation (without enzymes) significantly netics studies are conducted for digestion and absorption inves- decreased the bioaccessible phenolic content of some grains but tigations (Carbonell-Capella et al., 2014). Among them, in vitro increased their antioxidant activity. This implies that gastrointesti- simulated digestion process is the most widely utilized approach nal digestion may not only break down food matrices and release to predict the digestibility due to its low cost, high efficiency, and phenolic compounds by pH/enzyme effects but may also modify simple operation. A recent HPLC-MS analysis on lingonberries phenolic hydroxyl group (major functional group with effects on phenolic products in different digestion methods confirmed that antioxidant activity) of the released phenolics which would lead to similar metabolism patterns occurred within in vivo and in vitro a decrease or an increase of phenolics content and activity in the digestion process which shows the reliability of in vitro digestion final simulated digestion fluid (Table 4) (Bugianesi et al., 2004; (Brown et al., 2014). Chen et al., 2013; Chiang et al., 2013; Hithamani and Srinivasan, Several in vitro stimulated digestion results of plant foods are 2014; Kamiloglu et al., 2015; Li et al., 2014; Sessa et al., 2011; presented in Table 1. Based on the components studied, the sim- Tagliazucchi et al., 2010; Vallejo et al., 2004). ulated conditions especially the application of the enzymes and digestion time must be considered for each specific food sample. According to standardized digestion condition of Minekus et al. 2.2. Absorption in the gastrointestinal tract (2014) (Table 1), the primary simulated digestion includes a three- stage process given below. Understanding the absorption of dietary phenolics is of funda- 1. Simulated oral treatment with a final amylase activity of 75 mental importance in determining their biological activity. This is

Journal of Food Bioactives | www.isnff-jfb.com 13 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. because the degree of absorption from the diet profoundly affects was no actual absorption of proanthocyanidin trimers (Appeldoorn bioactivities at phenolics-responsive sites within the body (Day et et al., 2009; Deprez et al., 2001). al., 2003). On the basis of the preceding and other available literature, animal models and human experiments are essential as they provide accurate information. The study of in vitro absorption of catechin 2.2.1. Absorptivity by in vitro, in situ and in vivo methods and tannic acid in ligated rat small intestine segments showed that both tannic acid (50%) and catechin (30%) could enter into the The in vitro simulated digestion enables further study of gastroin- small intestinal cells, but only catechin (10%) passed through the testinal absorptive efficiency. For the in vitro absorptivity evalu- gut wall and arrived into the incubation buffers whilst no tannic ation, the dialysis method is usually employed as a simulated acid was detected (Carbonaro et al., 2001). In the human experi- intestinal epithelial cell layer to separate the pervious/absorbable ment, 53% of ingested quercetin (4 g) and 98% of chrysin (0.4 g) fraction from the digestion fluid (Table 5). The dialysis membrane were detected in the feces (Gugler et al., 1975; Walle et al., 2001). used is a semipermeable cellulose membrane with uniform pores Genistein absorption was also investigated by using rat small intes- allowing phenolics to pass via free diffusion. Based on free diffu- tine perfusion model in which genistein solution was perfused into sion mechanism which is one of the main absorption pathways of isolated rat small intestine; genistein was recovered from vascular phenolics, low-molecular-weight phenolics are easy to pass, and perfusion media, blood vessel, intestine tissue, and non-absorbable molecular weight of phenolics more than the cut-off molecular effluent. The results indicated 99.8% recovery, and 46% of gen- weight of dialysis membrane would be important about what is istein could be absorbed. Among absorbed genistein, about 40% of retained. The ratio of the penetrable fraction to the total content it came from vascular perfusion media, 6% was from blood vessels of such composition in raw materials is the predicted absorptivity. and the intestinal tissue (Andlauer et al., 2000). Griffiths and Smith The cut-off molecular mass of this semipermeable cellulose mem- (1972) and Booth et al. (1956) reported that the C-ring cleavage brane is usually around 10 kDa (Hemery et al., 2010; Hithamani caused by intestinal bacterial flora had a preference for flavonoids and Srinivasan, 2014; McDougall et al., 2005). with hydroxyl group in positions 5 and 4, such as apigenin, gen- Human colon cell lines such as Caco-2 and HT-29 cells are also istein, quercetin, rutin, kaempferol, robinin, and pelargonin, but prevalently used in bioaccessibility assays (Hackman et al., 2008; on the contrary, apigenin 4-methyl ether, 4′,7-dihydroxyflavone, Martin and Appel, 2009). Through in vitro simulated absorption daidzein, 5-methoxyquercetin, chrysin, tectochrysin, biochanin A experiments by using cell lines, the absorption efficiency and fac- and formononetin were relatively resistant to ring fission. How- tors affecting it could be clarified.Boyer et al. (2005) used Caco-2 ever, Andlauer et al. (2000) reported that no cleavage happened on cell monolayer to investigate the uptake of quercetin and quercetin- genistein during small intestinal absorption. Thus the intestinal mi- 4′-glucoside with/without digestion pre-treatment. Data shows that crobial ring fission effects should have only happened in the large the ingested dosage affects the absorption of flavonoids. Stand- intestine. The absorption of phenolic oligomers depends on their ards of quercetin and quercetin-4′-glucoside at high concentrations degree of polymerization; some with low-polymerization degree resulted in higher uptake than that of diluted ones and compared could be absorbed in the stomach and the small intestine by pas- to undigested fraction, the digested quercetin, and quercetin-4′- sive diffusion, others with a high-polymerization degree could not glucoside showed a higher uptake. Besides, it was demonstrated be absorbed until undergoing fermentation and degradation by co- that the lactase expressed exclusively by mammalian small intes- lonic bacteria. For example, monoferluate ester and diferulate ester tine enterocytes could hydrolyze quercetin-4′-glucoside into its standards could be absorbed in rat upper intestine, and ferulic acid aglycone and then increase the absorption of total phenolics. could be absorbed by gastric mucosa (Andreasen et al., 2001b). On the other hand, even if the combination of in vitro diges- However, procyanidin A-type trimers and tetramers were absorbed tion and dialysis methods provides rapid and predictive data for by small intestine in the rat perfusion model, instead of which, food digestion and absorption, the actual operation of the diges- procyanidin dimers A1, A2, and B2 were available to be absorbed. tive system and body physiological responses are complicated and Meanwhile, the absorptivity of all dimers was extremely low, only difficult to be completely simulated. Meanwhile, the study of the about 5–10% of that of epicatechin, even though A1 and A2 were correlation between in vitro and in vivo results is sometimes con- absorbed better than B2 (Appeldoorn et al., 2009). As Manach tradictory. For example, the absorption of quercetin glucosides in et al. (2005) summarized, the orally administrated anthocyanins the Caco-2 cell line was fairly low compared to that of quercetin presented the lowest gastrointestinal absorbability (0.004–5.1%) aglycone, and the apical-to-basal transporting rate of both querce- compared to other phenolics such as isoflavones (4–62%), fla- tin and its glycosides are much higher than their basal-to-apical vanones (1.1–30.2%), flavonols (0.07–7%), flavanols (0.02–55%) transporting rate, which shows it is unavailable for the absorption and phenolic acids (0.3–61.7%). of quercetin glucosides through active transportation in Caco-2 cell lines (Walgren et al., 1998). However, it is unexpectedly found that the absorption of glycosides was higher than that of aglycones 2.2.2. Influx transport of enterocytes in in vivo absorption experiment conducted by human ileostomy skill (Day et al., 2003; Hollman et al., 1995). This result was con- The uptake of phenolics occurs in a highly complex manner firmed in a pharmacokinetic study two years later by Hollman et through multiple pathways. Normally, similar to all fat-soluble mi- al. (1997). The main reason for this observation was regarded to be cromolecules, the relatively neutral or hydrophobic phenolics such active transporting of glycosides. Moreover, the pharmacokinetic as phenolic lipids, proanthocyanidins, artificial phenolic esters, study of anthocyanins showed that only about 1% could reach sys- (iso)flavonoid and lignan aglycones could be passively diffused tematic circulation, while the cellular study reported that 3–4% of through apical membrane of the epithelial cell (Domínguez-Avila them got through human intestinal cell monolayers (Faria et al., et al., 2017; Kobayashi et al., 2013). The penetration efficiency is 2009; Lee et al., 2014). In simulated absorption test by Caco-2 decided by their lipophilicity. For example, the revealed affinity of monolayer, the proanthocyanidin trimers could be absorbed and catechin derivatives to the lipid bilayer decreased in the order of showed the same permeability coefficients with catechin, proan- ECG > EGCG > EC > EGC (Tarahovsky et al., 2014). Generally, thocyanidin dimer, and mannitol, while in an animal model, there a lower pH suppresses ionization of phenolics and thus favors a

14 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds Table 1. Comparison of in vitro digestion method in bioaccessibility determination Materials Oral condition Gastric condition Small intestine condition References A Standardized Condition Food Sample 1:1 (v/v) Oral fluid 1:1 (v/v) Gastric 1:1 (v/v) Intestinal fuild Minekus et (amylase-75 U/ fluid (pepsin-2,000 (pancreatin based on al. (2014) ∼ ∼ ∼ mL): Sample, pH U/mL): Oral fluid, trypsin activity at 100 U/ 7.0, 2 min, 37 °C pH 3.0, 2 h, 37 °C mL, bile salts-10 mM): Gatric fraction, pH 7.5, 6 h, 37 °C Phenolics and Other phytochemicals Tea beverage (phenolics) Pepsin, pH 2.0, Pancreatin, Bile salts Chen et al. 1 h, 37 °C (glycodeoxycholate, (2013) taurodeoxycholate, taurocholate), pH 7.4 (transition pH 5.3), 2.5 h, 37 °C Grape seed extract Human saliva α- Pepsin, pH 2.0, Pancreatin, Bile salts, pH 7.0 Laurent et (flavonoids) Amylase in water 1 h, 37 °C (transition pH 6.0), 2 h, 37 °C al. (2007) with weak acid, pH 6.9, 10 min, 37 °C Wheat bread (flavonoids) Human saliva in buffer Pepsin, pH 1.2, Pancreatin, Bile salts, NaCl, Gawlik-Dziki (Na2HPO4, KH2PO4, 2 h, 37 °C KCl, pH 7.0 (transition et al. (2009) and NaCl), pH 7.0, pH 6.0), 1 h, 37 °C 10 min, 37 °C Soy bread (isoflavones) Human saliva in saline, Pepsin, pH 2.0, Pancreatin, pH 6.9, 2 h, 37 °C Walsh et al. pH 7.0, 5 min, 37 °C 1 h, 37 °C (2003) Millet grain (phenolics) Porcine α-amylase Pepsin, pH 2.5, Pancreatin, Mucin, Bile Chandrasekara in phosphate buffer, 2 h, 37 °C salts, pH 7.0, 3 h, 37 °C et al. (2012) pH 6.9, 5 min, 37 °C Raspberry (anthocyanins) Pepsin in water, pH Pancreatin, Bile salts, McDougall et 1.7, 2 h, 37 °C pH 7.0, 2 h, 37 °C al. (2005) Blueberry (phenolics) Pepsin in water, pH Pancreatin, Bile salts, Correa-Betanzo 2.0, 2 h, 37 °C pH 7.5, 2 h, 37 °C et al. (2014) Gooseberry (phenolics) Pepsin in water, pH Pancreatin, Bile salts Chiang et 1.7–2.0, 2 h, 37 °C (glycodeoxycholate, al. (2013) taurodeoxycholate, taurocholate), pH 8.0, overnight, 37 °C Various baby food Pepsin in water, pH Pancreatin, Bile salts, pH 7.5 Garrett et (carotenoids) 2.0, 1 h, 37 °C (transition pH 5.3), 2 h, 37 °C al. (1999) Various food (carotenoids Pepsin in saline, Pancreatin, Bile salts, Reboul et and tocopherol) Pyrogallol, pH pH 6.0, 0.5 h, 37 °C al. (2006) 4.0, 1 h, 37 °C Various food (tocopherol Pepsin in HBSS, lipase, Pancreatin, Bile salt O’Callaghan and retinol) pH 4, 1 h, 37 °C (glycodeoxycholate, taurocholate, et al. (2010) and taurodeoxycholate), pH 7.8 (transit pH 5.4), 2 h, 37 °C Broccoli (phenolics, Porcine pepsin in Pancreatin, Lipase, Bile Vallejo et glucosinolates, water, pH 2, 2 h, 37 °C salts, pH 7, 2 h, 37 °C al. (2004) ascorbic acid) Hemi-purified α-Amylase in water, Pepsin, pH 2, 2 h, 37 °C Pancreatin, Bile salts, Lai et al. (2010) glucoraphanin pH 7.0, 3 min, 37 °C pH 7.5, 2 h, 37 °C Soy flour (saponins) α-Amylase in PBS, pH Pepsin, pH 2.5, Pancreatin, Lipase, Bile salt Serventi et 7.0, 10 min, 37 °C 2 h, 37 °C (glycodeoxycholate, taurocholate, al. (2013) and taurodeoxycholate), pH 6.5, 2 h, 37 °C

Journal of Food Bioactives | www.isnff-jfb.com 15 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Table 1. Comparison of in vitro digestion method in bioaccessibility determination - (continued) Materials Oral condition Gastric condition Small intestine condition References Milk-based fruit α-Amylase, Mucin, Pepsin, BSA, pH Pancreatic lipase, Cholesterol Alvarez-Sala beverage (phytosterol) pH 6.5, 5 min, 37 °C 1.07, 1 h, 37 °C esterase, Phospholipase et al. (2016) A2, Colipase, Taurocholate, pH 7.0, 2 h, 37 °C Other Ingredients Triacylglycerol (cod liver oil) Lipase, Pepsin, pH Pancreatin, Bile Larsson et 2.0 (transition pH salts (glycocholate, al. (2012) 4.0 for another 30 glycochenodeoxycholate, min), 0.5 h, 37 °C glycodeoxycholate, taurocholate, taurochenodeoxycholate, taurodeoxycholate, taurolithocholate) Starch (variously Pepsin, pH 2.0, Pancreatin, α-Amylase, Wolf et al. (1999) modified starch and 0.5 h, 37 °C Amyloglucosidase, Acetate unmodified starch) buffer, pH 5.0, 37 °C Proteins (spelt products) Pepsin, pH 1.9, Pancreatin in Phosphate Abdel-Aal (2008) 0.5 h, 37 °C buffer, pH 7.5, 6 h, 37 °C Polysaccharides (seeds Human saliva in water, Pepsin, Lipase, Gastric Pancreatin, Trypsin, Bile Hu et al. (2013) of Plantago asiatica L.) pH 7.0, 4 h, 37 °C Electrolytes (NaCl, KCl, salts, Small intestinal CaCl2·2H2O, NaHCO3), electrolytes (NaCl, CaCl2·2H2O), pH 3.0, 6 h, 37 °C pH 7.0, 6 h, 37 °C

Iron (rye bread with FeCl3) Pepsin in saline, Pancreatin, Saline, pH Bering et al. L-lactic acid, Inositol 7.5, 6 h, 37 °C (2006) phosphates, pH 2.0, 1 h, 37 °C deeper penetration of phenolics into the lipid bilayer (Tarahovsky plant cells and mediate uptake of flavonoids such as epicatechin- et al., 2014). Meanwhile, multidrug and toxin extrusion transporter 3-O-glucoside and cyanidin-3-O-glucoside, using electrochemical I (MATE 1) greatly favor the intracellular accumulation of flavo- gradients across membranes (Lee et al., 2014; Zhao and Dixon, noid aglycones and corresponding glycosides in human hepatic 2009). Furthermore, some recent publications reported that the and renal cell, which is also found abundantly in the apical side polyspecific organic cation transporters: OCTN 1, OCT 1 and OCT of enterocytes (Lee et al., 2014; Matsson and Bergström, 2015). 2 are also involved in active transport of phenolics from extra- MATEs are a kind of bidirectional transporters that could exclude cellular fluid into various cells (Table 6) (Domínguez-Avila et al., substrates based on the electroneutral proton(H+)-coupled organic 2017; Estudante et al., 2013; Glaeser et al., 2014). After production cation exchange, extensively and abundantly expressed on the api- of primary urinary, OCT 1 facilitates the reabsorption of phenolic cal membrane of mammalian organ barriers including that of the cation on tubular apical (luminal) membrane, which shares an intestinal tract, as well as brain, kidney, liver and bile duct, which overlapped substrate-specificity for several toxic and therapeutic belong to the SLC47 superfamily. It is a vital efflux transporter in cationic compounds with MATE transporters (Volk, 2014; Winter urinary excretion (Lai, 2014; Lončar et al., 2016; Testa and Water- et al., 2010). beemd, 2007). However, Lee et al. (2014) reported that MATE 1 Compared with phenolic aglycones and other hydrophobic promoted the accumulation of intracellular flavonoids in MATE 1 phenolics, (iso)flavonoid glycosides present high water solubility. overexpressed cells, and flavonoids uptake decreased by 75% due Rather than free diffusion, glycosides are absorbed into intestinal to the addition of the MATE inhibitor. The known absorbability of cells by either active transport through sodium-dependent glucose aglycones via MATE 1 is in decreasing order of quercetin, kaemp- transporter (SGLT 1) or facilitated and transported by glucose ferol, luteolin, and apigenin, and it shows a higher affinity with transporter 2 (GLUT 2), or hydrolyzed to aglycones by lactase- flavonoid aglycone than its glycosides. Interestingly, during drug phlorizin hydrolase (LPH) and then passively diffused into en- metabolism in the human liver, bile duct, and kidney, MATE 1 terocytes. LPH is an endogenous β-glucosidase excreted outside mediates the excretion of metabolites from the cell to the extracel- the intestinal epithelial cell and bound on the intestinal mucosa lular fluids, urine and bile fluids (Lončar et al., 2016). It excludes surface; it is regarded as the major enzyme to hydrolyze phenolics various organic cationic compounds, such as tetraethylammonium, glycosides into phenolic aglycones before absorption onto mam- 1-methyl-4-phenylpyridinium and metformin, and some anionic malian intestinal brush border. LPH has two catalytic sites, one compounds such as estrone sulfate, acyclovir, and ganciclovir, is to hydrolyze lactose and the other is involved in the deglyco- out of cells (Astorga et al., 2012; Tanihara et al., 2007). There- sylation of more hydrophobic substrates, such as phlorizin, and by, it may imply the possibility that phenolics were absorbed by various flavonol/isoflavone glycosides. It has been reported the −1 MATE 1 with the efflux of endogenous or exogenous ions in pro- catalytic efficiency (kcat/Km) of quercetin-4′-glucoside (170 mM gress. However, the specific mechanism still needs to be studied. s−1), quercetin-3-glucoside (137 mM−1 s−1), genistein-7-glucoside MATE’s orthologs could also be found in vacuolar membranes of (77 mM−1 s−1), daidzein-7-glucoside (14 mM−1 s−1), phlorizin (257

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Table 2. Release evaluation of phenolics duringin vitro digestion

Release percentage of phenolics (%) Release Total phenolics Sample Oral phase References Gastric phase Intestinal phase standard extraction Apple Phenolics (68) Phenolics (74) Solubility Pure methanol (Bouayed et homogenate Flavonoids (65) Flavonoids (72) Ultrasonication al., 2011) Anthocyanins (91) Anthocyanins (0) Phenolics (54) Dialyzability Flavonoids (39) Anthocyanins (0) Orange juice Flavanones (51) Flavanones (51) Solubility Direct Gil-Izquierdo Vicenin-2 (117) Vicenin-2 (111) determination et al. (2001) Flavonones (6) Dialyzability Vincenin-2 (22) Pumpkin Phenolics (29–37) Solubility Free: HCl, water, Aydin and flour and methanol Gocmen. (1:80:10); (2015) Bound: H2SO4 and methanol (1:10) Grape 50% phenolics Phenolics (61) Phenolics (62) Solubility Free: acidified Tagliazucchi 27% flavonoids Flavonoids (43) Flavonoids (56) water et al. (2010) 19% anthocyanins Anthocyanins (36) Anthocyanins (8) Bound: acidified methanol Green lentil Phenolics (21) Phenolics (50) Solubility Acidified 70% Zhang et Flavonoids (29) Flavonoids (71) methanol al. (2017) Grape Phenolics (102) Phenolics (67) Solubility Acidified pure Wang et pomace methanol; al. (2017) 70% acetone Globe 27% caffeoylquinic Caffeoylquinic acid Caffeoylquinic acid Solubility 100% Water D’Antuono artichoke acid and and dicaffeoylquinic and dicaffeoylquinic et al. (2015) dicaffeoylquinic acid (36) acid (55.8) acid Pili pomace Phenolics (12) Phenolics (6) Solubility Acidified 50% Arenas and Flavonoids (0.7) Flavonoids (0.2) ethanol Trinidad Tannins (3.2) Tannins (1.2) (2017) Anthocyanins (200) Anthocyanins (10) Black bean Phenolics (24) Solubility Acidified Sancho et coat Flavonoids (82) pure water al. (2015) Tannins (6) Acidified pure methanol Small red Phenolics (49) bean coat Flavonoids (95) Tannins (7) Kale Phenolics (69) Solubility Hexane; Yang et al. Acetone; (2018) Methanol, water and formic acid (80:19:1) mM−1 s−1) and lactose (4 mM−1 s−1) (Day et al., 2000b). This en- which is the glucose transporter highly expressed on the apical zyme is more important for humans than other mammals in the membrane of small intestinal epithelial cells and proximal tubule digestion of β-glycosides because of the absence of gastric micro- of the nephron, was responsible for glucose/galactose absorption organism and other hydrolysis enzymes in the human intestinal and reabsorption. This transporter may actively favor the absorp- tract (Day et al., 2000b). tion of monoglycoside phenolics due to its preferred transportation Hollman et al. (1995) indirectly demonstrated that SGLT1, of glucose/galactose moiety. As a result, monoglycoside phenolics

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Table 3. Effects of ingested quantity on anthocyanins bioaccessibility in black carrot pomace enriched cakes Released anthocyanin (%) Sample (mg/g, dw) Total phenolics extraction References Gastric phase Intestinal phase Cyanidin-3-xylosyl- 5 (C3G)a 40.0 32.0 70% methanol with 0.1% Kamiloglu et al. (2017) glucosyl-galactoside formic acid; Ultrasonication 12 (C3G) 75.0 41.7 20 (C3G) 55.0 30.0 Cyanidin-3-xylosyl-galactoside 19 (C3G) 62.9 11.6 52 (C3G) 38.5 21.2 75 (C3G) 30.7 18.7 Cyanidin-3-xylosyl-sinapoyl- 11 (C3G) 27.3 45.5 glucosyl-galactoside 27 (C3G) 48.1 44.4 48 (C3G) 39.6 31.2 Cyanidin-3-xylosyl-feruloyl- 32 (C3G) 29.2 40.6 glucosyl-galactoside 77 (C3G) 57.1 42.9 111 49.5 46.8 (C3G) Cyanidin-3-xylosyl-coumaroyl- 5 (C3G) 20.0 40.0 glucosyl-galactoside 13 (C3G) 46.2 30.8 13 (C3G) 61.5 61.5 aC3G: cyaniding-3-O-glucoside equivalent. present a faster and higher absorption rate than other phenolics with quercetin-4′-glucoside (170 mM−1s−1), quercetin-3-glucoside without active transportation, and are regarded as the competi- (137 mM−1s−1), and genistein-7-glucoside (77 mM−1s−1), even tive substrates for glucose transport by SGLT1 at the same time though all of them are β-glucosides (Day et al., 2000b; Hollman, (Cermak et al., 2004; Gee et al., 2000; Goto et al., 2012; Holl- 2004). The GLUTs protein family belongs to the major facilitator man et al., 1995). Meanwhile, Hossain et al. (2002) found that superfamily (MFS) of membrane transporters; they are unidirec- non-glycosylated phenolics such as catechin, epicatechin gallate tional transporters which favor not only glucose but also phenolic (ECG) and epigallocatechin gallate (EGCG) also inhibited SGLT aglycones and/or phenolic glycosides to enter into the cells by fa- 1 response of glucose/galactose absorption. Moreover, the trans- cilitated transport (Passamonti et al., 2009). GLUT 2 is highly ex- portability for monoglycoside phenolics depends on their specific pressed on the basal side of the intestinal cell, which was reported structure. The transport of quercetin-3/4′-O-glucoside by SGLT 1 to transport quercetin-3-O-glucoside out of the basal side of Caco- is available while for that of non-glucosylated phenolics and some 2 cells, but it is unavailable for ECG (Chen et al., 2007). Faria et other monoglycoside phenolics (naringenin-7-O-glucoside and al. (2009) reported that anthocyanins inhibit the uptake of glucose genistein-7-O-glucoside) may not be (Cermak et al., 2004). In the by upgrading the expression of GLUT 2. Besides, combined with intestine, LPH protrudes into an unstirred boundary layer and is other GLUT members (GLUT 1 and 4), the flavonoid aglycones positioned in close proximity to the SGLT 1. An animal experi- and non-glycosylated polyphenols are regarded as competitive ment was conducted to verify absorption pathway of quercetin by substrates for each other in facilitated transport by GLUTs, similar Day et al. (2003) who utilized inhibitors to block each pathway, to the situation that flavonoid glycosides inhibit glucose absorption respectively, and proved both of these two pathways: active trans- by SGLT 1 (Ashong et al., 2012; Faria et al., 2009). port by SGLT 1 and passive diffusion by LPH, as being responsible Besides LPH, cinnamoyl esterases may provide another vital for absorption of quercetin glucoside. Meanwhile, data shows the route for the release of phenolic aglycones from ester bond of pathway of flavonoid glycosides with different structures is varied, polysaccharides and phenolic polymers during small intestinal quercetin-4′-glucoside is absorbed by both interacting with SGLT digestion. Cinnamoyl esterases are well known as gut microbial 1 and luminal hydrolysis by LPH, while absorption of quercetin- enzymes excreted during colonic fermentation, but it has also been 3-glucoside involves only LPH. This result was also confirmed in found in both small intestinal mucosa cell and lumen (Andreasen in situ rat perfusion model that LPH was predominantly (>75%) et al., 2001a). The presence of esterase activity in these sections involved in the absorption of quercetin-3-glucoside in the small of the intestinal tract was found in which ferulic and p-coumaric intestine (Sesink et al., 2003). However, within various glycoside acids were released from spinach cell walls and might be absorbed forms including C–O glycosides such as glucosides, galactosides, through the stomach and small intestine of rat (Buchanan et al., arabinosides, xylosides and rhamnosides, and C–C glycosides 1996). This thought was verified 5 years later by extracting cin- conjugating with flavonoids, only β-glucosides could effectively namoyl esterases from the surface of the rat and human small in- be hydrolyzed by LPH. Meanwhile, low or even none hydrolysis testine. The phenolic acids esters especially methyl hydroxycin- extent was found during the absorption of daidzein-7-glucoside namoyl esters (monoferluate ester, diferulate ester, p-coumaric (14 mM−1s−1) and cyanidin-3-glucoside (0 mM−1s−1), compared acid, methyl ferulate, methyl caffeate, and methyl sinapate) ex-

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Table 4. Stability of phenolic compounds during gastrointestinal digestion Phenolics loss (%) Digested material References Gastric phase Intestinal phase Phenolic standards Gallic acid (35.0 μg/mL) 4.6a 43.3 Tagliazucchi et Caffeic acid (8.0 μg/mL) 0.1a 24.9 al. (2010) Catechin (40.0 μg/mL) 0.7a 7.2 Quercetin (60.0 μg/mL) 0.9 5.8 Resveratrol (3.0 μg/mL) −2.3 69.5 Cyanidin 3-rutinoside (52.8 μg/mL) 0 9.1 Bermúdez-Soto Quercetin-3-rutinoside (160.6 μg/mL) 0 3.1 et al. (2007) (+)-Catechin (320.0 μg/mL) 3.1 58.0 Chlorogenic acid (90.0 μg/mL) 0 5.1 Chlorogenic acid (100.0 μg/mL) 48.1 D’Antuono et 1,5-O-Dicaffeoylquinic acid (100.0 μg/mL) 49.6 al. (2015) 3,5-O-Dicaffeoylquinic acid (100.0 μg/mL) 25.8 Chlorogenic acid (67.5 μg/mL) 58.1 95.7 Siracusa et Rutin (45.0 μg/mL) 88.1 total al. (2011) Quercetin 3-O-glucoside (30.0 μg/mL) total total Quercetin (15.0 μg/mL) total total Pelargonidin-3-glucoside 1.0 19.0 Woodward et Cyanidin-3-glucoside 2.0 67.0 al. (2011) Pelargonidin 8.0 36.0 Cyanidin 10.0 34.0 Phenolic extracts Mulberry phenolic extracts Anthocyanins 1.6 95.1 Liang et al. (2012) Phenolics 39.6 38.0 Rose phenolic extracts Phenolics 6.2 15.7 Zhang et al. (2016) Caper phenolic extracts Chlorogenic acid (3.3 μg/mL) 5.8 33.0 Siracusa et 4-Caffeoylquinic acid (1.8 μg/mL) 1.5 26.4 al. (2011) 5-Coumaroylquinic acid (0.5 μg/mL) 3.9 25.7 4-Feruloylquinic acid (0.7 μg/mL) 2.5 19.8 Rutin (10.2 μg/mL ) 1.7 total Quercetin 3-O-glucoside (0.2 μg/mL ) 3.8 total Kaempferol 3-O-rutinoside (2.3 μg/mL ) 5.0 total Isorhamnetin 3-O-rutinoside (0.8 μg/mL ) 2.3 total Kaempferol 3-O-glucoside (0.6 μg/mL ) 6.6 total Sea Fennel phenolic extracts 3-Caffeoylquinic acid (12.0 μg/mL ) total total Chlorogenic acid (198.6 μg/mL ) 66.0 81.7 1-Caffeoylquinic acid (24.3 μg/mL ) 67.4 78.1 5-p-Coumaroylquinic acid (16.6 μg/mL ) total total 5-Feruloylquinic acid (25.0 μg/mL ) total total 3,4-Dicaffeoylquinic acid (15.6 μg/mL ) total total 3,5-Dicaffeoylquinic acid (57.1 μg/mL ) total total 4,5-Dicaffeoylquinic acid (29.6 μg/mL ) total total

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Table 4. Stability of phenolic compounds during gastrointestinal digestion - (continued) Phenolics loss (%) Digested material References Gastric phase Intestinal phase Grape pomace Galloylshikimic acid (3.4 mg/g) total Corrêa et al. (2017) phenolic extracts Proanthocyanidine B dimer (25.4 mg/g) 91.4 Digalloylquinic acid (2.3 mg/g) 95.2 (-)-Epicatechin (7.3 mg/g) 76.3 (+)-Catechin (7.3 mg/g) 75.7 Digalloylshikimic acid (1.9 mg/g) Total Proanthocyanidine B trimer (8.5 mg/g) 93.4 Proanthocyanidine B tretramer (6.2 mg/g) 93.9 Myricetin-O-hexoside(1.4 mg/g) 19.7 Quercetin-3-O-glucuronide(0.6 mg/g) Total Quercetin-3-O-glucoside(0.5 mg/g) 55.8 Laricitrin-O-hexoside(0.4 mg/g) total Quercetin-O-pentoside(0.4 mg/g) total Quercetin-O-rhamnoside(0.4 mg/g) 36.8 Isorhamnetin-3-O-glucoside(0.5 mg/g) total Methylisorhamnetin derivative(0.3 mg/g) total Total non-anthocyanin 87.5 compounds(66.6 mg/g) Petunidin-3-O-glucoside (0.6 mg/g) 68.9 Peonidin-3-O-glucoside (1.6 mg/g) 85.4 Malvidin-3-O-glucoside (3.4 mg/g) 90.0 Peonidin-3-O-acetylglucoside (0.7 mg/g) 74.1 Malvidin-3-O-acetylglucoside (0.7 mg/g) 73.9 Total anthocyanin compounds (7.0 mg/g) 84.0 Food matrix Chokeberry juice concentrates Cyanidin 3-galactoside (362 μg/mL) −3.3 39.2 Bermúdez-Soto Cyanidin 3-glucoside (41.6 μg/mL) −3.8 43.3 et al. (2007) Cyanidin 3-arabinoside (240 μg/mL) −2.3 44.9 Cyanidin 3-xyloside (29 μg/mL) −4.1 50.8 Cyanidin (7.2 μg/mL) −350 total Quercetin hexoside pentoxide (22.4 μg/mL) 4.5 28.6 Quercetin 3-galactoside (27 μg/mL) 2.2 15.5 Quercetin 3-glucoside (37.2 μg/mL) 7.0 19.1 Quercetin 3-rutinoside (88.8 μg/mL) 5.9 29.6 Quercetin (3.6 μg/mL) −5.6 Total Neochlorogenic acid (318 μg/mL) 3.8 28.0 Chlorogenic aid (296 μg/mL) 3.4 −23.9 Other flavan-3-ols (710 μg/mL) 14.9 19.3 Strawberry yoghurt (+)-Catechin (534.8 μg/g) 10.9 47.0 Oliveira and Quercetin-3-rutinoside (11.0 μg/g) 18.2 40.0 Pintado (2015) Ellagic acid (8.6 μg/g) 7.0 3.5 Cyanidin-3-glucoside (6.5 μg/g) −3.1 46.2

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Table 4. Stability of phenolic compounds during gastrointestinal digestion - (continued) Phenolics loss (%) Digested material References Gastric phase Intestinal phase Pelargonidin-3-glucoside (70.6 μg/g) −11.6 65.3 Pelargonidin-3-rutinoside (6.7 μg/g) −26.7 58.2 Peach yoghurt (+)-Catechin (35.5 μg/g) 20.6 80.0 Neochlorogenic acid (50.4 μg/g) −8.5 45.0 Chlorogenic acid (46.4 μg/g) −9.9 38.6 Quercetin-3-rutinoside (7.7 μg/g) −7.8 31.2 aOne stage overall process only. tracted from cereal bran was found to be efficiently hydrolyzed of basolateral sodium/potassium pumps of enterocytes also actively by these esterases. The known catalytic efficiency is in decreasing transporting various short chain fatty acids into endothelial cells, it order of methyl p-coumarate, methyl ferulate, methyl caffeate and is mainly expressed in the intestine rather than the stomach (Zie- methyl sinapate (Andreasen et al., 2001a). However, the same au- gler et al., 2016). Meanwhile, paracellular transport was proposed thors reported that ferulic acid was hardly absorbed by the small in- to serve as the absorption mechanism of the phenolic acids (An- testinal epithelial cells by transcellular transport. Owing to the ioni- derson, 2001; Domínguez-Avila et al., 2017; Konishi et al., 2003). zation of phenolic acid in the alkalescent intestinal fluid, phenolic Different from all the transcellular transport ways described above, acid anions in the small intestine are theoretically less available to the paracellular pathway happens on intercellular tight junctions passively diffuse through the intestinal mucosa (Andreasen et al., which is a narrow gap that separates the neighboring enterocytes by 2001b). Instead, Lafay et al. (2006) found that intact chlorogenic certain proteins called claudins (Anderson, 2001). The low selec- acid molecules could be fast absorbed in rat stomach, proved by tivity of these proteins (resistance varies by 100,000-fold between infusing phenolics into the ligated stomach of food-deprived rats. “tight” and “leaky” epithelia) allows not only susceptible passing Meanwhile, stomach was demonstrated to be an effective site for of hydrophobic and neutral molecules, but also the permeation of absorption of phenolic acids, as well as for absorption of quercetin, hydrophilic molecules that are unable to permeate through the lipid daidzein, and anthocyanins, even if neither quercetin 3-O-glucoside membrane by the transcellular pathway of absorption (Anderson, nor rutin was absorbed from the stomach (Crespy et al., 2002; Pas- 2001). It provides the theoretical support why small-mass phenolics samonti et al., 2003; Piskula et al., 1999). However, according to that are charged, such as ferulic, chlorogenic, gallic and rosmarinic Andreasen et al. (2001b), there were no data to support the non- acids, were observed in vivo before they enter into the colon (Koni- absorbability of phenolic acid in the intestine by passive diffusion. shi et al., 2004a; Konishi et al., 2005; Konishi et al., 2006). The In contrast, more novel absorption ways of phenolic acids and their colonic metabolite of phenolic acids, 3,4-dihydroxyphenylpropi- anions were raised in addition to free diffusions, such as active onic acid, was found to be absorbed via paracellular transport as transport and paracellular transport. Monocarboxylic acid trans- well as via MCT transporters. However, compared with that of phe- porters (MCT) are a kind of important active transporter of SLC16 nolics transported by both transcellular and paracellular ways, the superfamily that could be expressed on the apical membrane of absorbability of phenolics only transported through paracellular is gastric and intestinal epithelial cell, as well as various other tissue much lower, namely a quite low absorbability for phenolic acids cells. They play a major role in cell metabolism and metabolic com- by paracellular pathway (Konishi et al., 2004b, 2005; Lafay and munication between tissues (Dhananjay et al., 2013). MCT prefer Gil-Izquierdo, 2008). to favor molecules with one carboxylate group to penetrate through These aforementioned phenolic transporters are expressed the plasma membrane, thus possess a high affinity with phenolic not only in the digestive tract but also other blood-tissue barri- acids and corresponding anions especially those with relatively ers shown in Table 6. Meanwhile, some transporters cannot be lower polarity. Konishi et al. (2004, 2006) investigated the gastric found in the gastrointestinal cell but present in other tissues such absorption based on MCT of several phenolic acids which is in the as renal medulla which is involved in the intake of phenolics and order of gallic acid = chlorogenic acid < caffeic acid < p-coumaric corresponding metabolites from extracellular fluid and urine. They acid = ferulic acid. Surprisingly, besides phenolic acids, quercetin are glucose transporters (GLUT 1 and GLUT 4), organic anion and ECG (epicatechin gallate) could also penetrate the apical mem- transporters (bilitranslocase, OAT 1, OAT 3 and OAT 4), and or- brane through MCT (Contreras et al., 2016; Walle, 2004). MCT 1 ganic anion transporting polypeptides (OATP1A2 and OATP2B1). is the best-known member of the MCT family and has been veri- GLUT 1 could be found in erythrocytes, brain, placenta, adipose fied as a transporter of phenolic acids in the intestinal mucosa. It cell, and muscle, and GLUT 4 is extensively distributed in the is expressed on both sides of the intestinal cell and transports phe- brain, muscle, heart, and adipose cell and is insulin sensitive; their nolics especially phenolic acids from the lumen and extracellular transportability of phenolics depends on substrate concentration fluid into enterocytes (Ziegler et al., 2016). Watanabe et al. (2006) gradient (Wood and Trayhurn, 2003). Bilitranslocase is a kind of reported that MCT 1 was involved in the uptake of salicylic acid bilirubin active transporter found on the liver plasma membrane but not p-coumaric acid and fluorescein, thus they doubted the phe- and is also broadly distributed in other epithelium or endothelium nolics transportability of MCT 1. Meanwhile, some contradictory barriers of the kidney, digestive tract, blood vessel, and brain. It is reports about localization (only apical or only basal membrane) of found to have a high affinity for various dietary flavonoids espe- MCT 1 were compared in this study. Apart from MCT, sodium- cially the glycoside-type. In a previous report, a total of 17 antho- coupled monocarboxylate transporter 1 (SMCT1) has also been cyanidins and their mono- and diglycosides presented interaction suggested as the efflux transporter of phenolic acids, which is a kind effect on transport site of bilitranslocase which prefer to capture hy-

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Table 5. In vitro absorption evaluation by dialysis Dialyzed Sample Absorption medium Method Source rate (%) Apple Phenolics 55 10 kDa dialysis membrane Bouayed et al. (2011) Flavonoids 38 Orange juice Flavanone 12–36 12 kDa dialysis membrane Gil-Izquierdo et Narirutin 11–31 al. (2001) Hesperidin 16–37 Vicenin-2 19–30 Orange juice Flavanone 12–20 12 kDa dialysis membrane Gil-Izquierdo et Narirutin 12–21 al. (2002) Hesperetin 12–21 Vicenin-2 13–22 Strawberry Cyaniding-3-glucoside 0–6 Pelargonidin-3-glucoside 1–13 Pelargonidin rutinoside 1–12 Ellagic acid arabinoside 5–21 Ellagic acid 6–173 Quercetin-3-glucoside 4–28 Kaemferol-3-glucoside 19–27 Strawberry jam Cyaniding-3-glucoside 0–2 Pelargonidin-3-glucoside 1–4 Pelargonidin rutinoside 1–4 Ellagic acid arabinoside 6 Ellagic acid 6–10 Quercetin-3-glucoside 5–6 Kaemferol-3-glucoside 12–27 White or Whole-meal Bread Ferulic acid 61–77 Unknown dialysis membrane Anson et al. (2009) p-Coumaric acid 63–78 Sinapic acid 89–92 Whole-meal Bread Ferulic acid 2.5–5.1 5–8 kDa dialysis membrane Hemery et al. (2010) p-Coumaric acid 5.9–15 Sinapic acid 20–60 Soymilk Flavonoids 15 12 kDa dialysis membrane Rodríguez-Roque Phenolics 20 et al. (2013a) Hesperidin 14 Naringenin 21 Quercetin 17 Catechin 28 Rutin Gallic acid p-Hydroxybenzoic acid 0 p-Coumaric acid Ferulic acid Sinapic acid

22 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Table 5. In vitro absorption evaluation by dialysis - (continued) Dialyzed Sample Absorption medium Method Source rate (%) Mixed fruit juice Phenolics 12 12 kDa dialysis membrane Rodríguez-Roque Caffeic acid 0 et al. (2013b) Chlorogenic acid 11 p-Coumaric acid 17 Ferulic acid 26 Sinapic acid 18 Hesperidin 18 Naringenin 19 Rutin 22 Quercetin 29 Catechin 23 Durum Wheat Bran Ferulic acid 32 12 kDa dialysis membrane Zaupa et al. (2014) p-Coumaric acid 100 Sinapic acid 79 Caffeic acid 52 p-Hydroxybenzoic acid 98 Cooked finger Millet Phenolics 16–37 10 kDa dialysis membrane Hithamani and Flavonoids 15–50 Srinivasan (2014) Cooked pearl Millet Phenolics 73–96 Flavonoids 6–52 Raspberry Phenolics 10 12 kDa dialysis membrane McDougall et Anthocyanins 5 al. (2005) Maqui berry Rutin 2.2 12–14 kDa dialysis Lucas-Gonzalez Ellagic acid 0.3 membrane et al. (2016) Quercetin-3-O-galactoside 4.9 Dimethoxy-quercetin 0.04 Delphinidin-3-sambubioside- 5-glucoside Delphinidin-3,5-diglucoside Delphinidin-3-glucoside Cyanidin-3,5-diglucoside Delphinidin-3-sambubioside Cyanidin-3-glucoside Cyanidin-3-sambubioside 0 Cyanidin-3-sambubioside-5-glucoside Myricetin-3-galactoside Myricetin-3-glucoside Quercetin-galloyl-hexoside Quercetin-3-glucoside Quercetin-3-xyloside Myricetin Quercetin Mulberry extracts Anthocyanins 0.34 3.6 kDa dialysis membrane Liang et al. (2012) Phenolics 7.33

Journal of Food Bioactives | www.isnff-jfb.com 23 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. . References (2015), and Bergström Matsson (2003), Chen and Jonker Schinkel al. et al. (2016), Kobayashi et al. (2000) et (2013), Kullak-Ublick al. et Milbury (2009), Wu (2011), Russel (2010) . al. et Milbury (2009), Wu (2011), Russel (2010) . (2003), and Jonker Schinkel al. (2016), Kobayashi Chen et al. (2013), Sandusky et et al. (2002), Russel (2010) Phenolic substrates phenolic anions: and unconjugated Conjugated qucertin/resveratrol/ daidzein quercetin, curcuminoids) acid conjugates, naringenin/ferulic phenolic anions and unconjugated Conjugated phenolic anions and unconjugated Conjugated phenolic and unconjugated Conjugated phloridzin, quercetin- anions (epicatechin, genistein-7-glucoside, 4′- β -glucoside, qucertin/resveratrol/ daidzein, quercetin, acid conjugates naringenin/ferulic Direction Efflux Efflux Efflux Efflux - expres Protein sion level Low ND-low Moderate-high Low Moderate Low Low — Low Moderate Moderate High Low-high Moderate Low Low Low High Moderate Moderate High Low-moderate Moderate Low Moderate Moderate Distribution Liver (basal) Liver (basal) Kidney Brain Adipose intestine Large (basal) (apical) Kidney Brain (basal) Stomach intestine Large (basal) (basal) Liver (basal) Kidney Heart islet Pancreatic muscle Skeletal (apical) Stomach intestine Large (apical) Liver (apical) Kidney Brain Adipose muscle Skeletal Large intestine intestine Large (basal) (basal) Liver Small intestine (basal) Small intestine (apical) Small intestine Small intestine (basal) Transporter Transporter name MRP 4 MRP 3 MRP 2 MRP 1 Encoding Encoding gene ABCC4 ABCC3 ABCC2 Active transporters ABCC1 Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table

24 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds . . . References (2015), and Bergström Matsson (2003), Chen and Jonker Schinkel al. et al. (2016), Kobayashi et al. (2000) et (2013), Kullak-Ublick and Bergström Matsson al. (2013), et (2015), Kobayashi al. (2013), Schinkel et Estudante al. (2003), Chen et and Jonker al. (2005) (2016), Sesink et al. (2016), Lafay Ziegler et (2008) and Gil-Izquierdo Phenolic substrates phenolic and unconjugated Conjugates (daidzein) cations phenolic cations, phenolic anions and unconjugated Conjugates acid/quercetin/ acid, ferulic (dihydroferulic quercetin, conjugates, resveratrol/genistein and coumestrol) daidzein, chrysin, anions Phenolic acid and phenolic conjugate Direction Efflux Efflux Efflux - expres Protein sion level Low Moderate Low Low Moderate Moderate moderate to Low Low Low Low Moderate Moderate Low-moderate Moderate Low-moderate High Moderate Low-moderate Low Low Low-moderate - (continued) Distribution intestine Large Liver (apical) Liver (apical) Kidney (apical) Brain Small intestine (both) (apical) Liver (apical) Kidney (apical) Brain Heart Smooth muscle Stomach intestine Large (basal) Liver Kidney Heart Smooth and muscle skeletal Brain Adipose Large intestine intestine Large (basal) Small intestine (basal) Small intestine Small intestine (apical) Transporter Transporter name BCRP MCT 4 MDR 1 Encoding Encoding gene ABCG2 SLC16A3 ABCB1 Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table

Journal of Food Bioactives | www.isnff-jfb.com 25 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. . . . References (2015), and Bergström Matsson al. (2016), Lafay Ziegler et (2008) and Gil-Izquierdo al. (2016), Poquet Ziegler et al. (2008), Cui and Morris et (2009), Rhoden (2012), et al. (2007) Martin Matsson and Bergström (2015), and Bergström Matsson al. (2014), Domínguez-Avila Lee et al. (2017), Russel (2010) et -coumaric m -coumaric hydroxyphenyl)propionic acids) m- hydroxyphenyl)propionic Phenolic substrates Phenolic acids, phenolic acid conjugate acid conjugate, acid, ferulic anions (ferulic acid, salicylic dihydroferluric and 3-( phenolic acid Sodium-coupled Cationic compounds efflux and phenolics influx* efflux and phenolics compounds Cationic apigenin. luteolin, kaempferol, (quercetin, and conjugates) phenolic glucosides to Less prefer Direction Influx Both Influx - expres Protein sion level Moderate-high High Moderate Moderate Low Moderate Low-moderate Moderate High Moderate Low Low Low Moderate-high Moderate High Low Low Low Low Low - (continued) Distribution Large intestine intestine Large (both) Liver Kidney Brain Heart Smooth and muscle skeletal Small intestine (both) Small intestine Small intestine (both) Stomach (apical) Stomach Large intestine intestine Large (both) Kidney (both) Kidney Brain Stomach intestine Large (apical) Kidney (apical) Liver Adipose Heart Smooth/skeletal muscle Brain Small intestine Small intestine (apical) Transporter Transporter name SMCT 1 MCT 1 MATE 1 MATE Encoding Encoding gene SLC5A8 SLC16A1 SLC47A1 Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table

26 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds . . . Passamonti et al. (2009), Passamonti al. (2009) et Maestro and al. (2012), Matsson Cheng et al. (2015), Glaeser et Bergström (2012), Cheng et (2014), Tamai al. (2000) al. (2012), Gao et (2015), and Bergström Matsson (2012), al. (2014), Tamai Glaeser et al. (2012), Grosser Cheng et al. (2015), Russel (2010) et al. (2015) et Grosser al. (2015) et Grosser References al. (2004), Sabino- Williams et al. (2010), Shi et et Silva al. et al. (2016), Walgren al. (2012) et (2000b), Yu β -glucoside) Phenolic glycosides and aglycones: and aglycones: Phenolic glycosides baicalein malvidin 3-glucoside, quercetin, hydrophobic phenolics, large Amphipathic anions, phenolic anions (quercetin) organic hydrophobic phenolics, large Amphipathic anions, phenolic anions organic daidzein-7-glucuronide) (quercetin, monosulfates Daidzein daidzein-7,4′-disulfates. monosulfates, Daidzein Phenolic substrates (phlorizin, calycosin-7-O- Phenolic glycosides 4′-O- quercetin β -D-glucoside Influx Influx Influx Influx Influx Direction Influx Low Low — — — — — — — — — Low Moderate-high High Moderate — — ND-Low Low Moderate Moderate Moderate Low Moderate Moderate - expres Protein sion level High - (continued) Kidney Brain Heart (apical) Stomach intestine Large (basal) Liver Kidney Brain Small intestine (apical) (basal) Liver (basal) Brain Stomach intestine Large (apical) (basal) Kidney (basal) Liver (basal) Brain Heart muscle Skeletal islet Pancreas Stomach Liver Small intestine (both) (both) Kidney Small intestine (apical) Liver (basal) Liver Distribution Small intestine Small intestine side) (apical Bilitranslocase OATP1A2 OATP2B1 SOAT NTCP Transporter Transporter name SGLT 1 SGLT - SLCO1A2 SLCO2B1 SLC10A6 SLC10A1 Encoding Encoding gene SLC5A1 Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table

Journal of Food Bioactives | www.isnff-jfb.com 27 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. . . Estudante et al. (2013), Glaeser et Estudante al. (2014), Russel (2010) et References et al. (2009), Passamonti (2013) . and Sweet Wang Wang and et al. (2009), Passamonti al. (2012), et (2013), Faria Sweet and Endou (2004) Koepsell Wang et al. (2009), Passamonti (2013), Kullak- and Sweet al. al. (2000), Chen et Ublick et al. (2015) et (2005), Grosser Low-molecular-weight phenolic cations phenolic cations Low-molecular-weight conjugates) and quercetin (quercetin Caffeic acid-3-O-sulfate, caffeic acid-4-O- caffeic acid-3-O-sulfate, Caffeic isoferulic acid-4-O-sulfate, ferulic sulfate, monosulfates daidzein acid-3-O-sulfate, Phenolic substrates anions (morin, Phenolic and phenolic conjugate acid-3-O- caffeic ferulic acid, acid, silybin, caffeic acid-4-O-glucuronide/ caffeic glucuronide/sulfate, acid, acid, dihydroferulic dihydrocaffeic sulfate, acid-3-O-glucuronide/sulfate, dihydrocaffeic acid-4-O-glucuronide/sulfate, dihydrocaffeic acid-4- ferulic acid-4-O-sulfate, dihydroferulic genistein-4′-O-sulfate/ O-glucuronide/sulfate, isoferulicacid-3-O-glucuronide/ glucuronide, quercetin-3′- quercetin-3-O-glucuronide, sulfate, quercetin-7-O-glucuronide) O-sulfate/glucuroside, anions (caffeic Phenolic and phenolic conjugate caffeic acid-3-O-glucuronide/sulfate, acid, caffeic dihydrocaffeic acid-4-O-glucuronide/sulfate, acid- acid, dihydrocaffeic acid, dihydroferulic acid- dihydrocaffeic 3-O-glucuronide/sulfate, acid-4- dihydroferulic 4-O-glucuronide/sulfate, acid-4-O-glucuronide/sulfate, ferulic O-sulfate, isoferulic genistein-4′-O-sulfate/glucuronide, quercetin-3-O- acid-3-O-glucuronide/sulfate, quercetin-3′-O-sulfate/glucuroside, glucuronide, daidzein-7-O- quercetin-7-O-glucuronide, genistein- daidzein-7,4′-O-disulfate, glucuronide, glycitein-7-O-glucuronide) 7-O-glucuronide, Influx Direction Influx Influx Low-moderate Low-moderate Moderate-High Low-moderate Low Moderate Moderate Low Low-moderate - expres Protein sion level High Low Low Low High Low — High Moderate-high - (continued) Large intestine intestine Large (basal) (basal) Liver (both) Kidney Brain Heart muscle Skeletal islet Pancreas Small intestine Small intestine (basal) Stomach Distribution (basal) Brain brain Muscle Adipose (basal) Kidney Mucsle Skeletal (apical) Kidney Liver Kidney (basal) Kidney OCT 1 Transporter Transporter name OAT3 4 OAT OAT 1 OAT SLC22A1 Encoding Encoding gene SLC22A8 SLC22A9/ SLC22A11 SLC22A7 Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table

28 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds . . . . . Passamonti et al. (2009), Passamonti (2003), and Trayhurn Wood al. (2006) Cunningham et et al. (2009), Passamonti (2003), and Trayhurn Wood Gould and Holman (1993), al. (1997) McCall et Wood et al. (2009), Passamonti (2003), Gould and Trayhurn and Holman (1993), Wenzel al. (2005), et (2013), Freitas al. (2014) et Fernandes References al. (2013), Faria et Estudante et al. (2012), Kullak-Ublick et al. (2007) al. (2000), Zhou et al. (2013), et Estudante al. (2017), et Domínguez-Avila al. (2004) et Koepsell quercetin quercetin, myricetin, Genistein, and catechin-gallate anthocyanins 3-glucoside, Quercetin Phenolic substrates phenolic cations Low-molecular-weight and anions phenolic cations Influx Influx Influx Influx Influx Influx Both Direction Influx Both — — — — Low Low ND-low Low Low Low high Moderate Low Moderate High Moderate Low Moderate - expres Protein sion level Low Moderate-high Moderate — Low - (continued) Large intestine intestine Large (apical) Liver Liver (only Liver apical) fetal, (apical) Kidney muscle Skeletal Brain Brain and Skeletal smooth muscle Brain Small intestine (both) (basal) Kidney islet Pancreas Adipose and Skeletal smooth muscle Erythrocyte Heart Liver Adipose Distribution Kidney (basal) Kidney (basal) Brain Small intestine (apical) Liver (basal) Liver Small intestine Small intestine (basal) GLUT 1 GLUT 2 GLUT GLUT 4 GLUT Transporter Transporter name OCTN 1 OCT 2 Facilitated transporters Facilitated SLC2A1 SLC2A2 SLC2A4 Encoding Encoding gene SLC22A4 SLC22A2 Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table

Journal of Food Bioactives | www.isnff-jfb.com 29 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

drophilic groups including glycosyl moiety and/or B/A rings of flavonoid glycosides and aglycones, thus deducing that bilitranslocase could play a role in the bioavailability of anthocyanins (Passamonti et al., 2002). Before long, two reports from the same lab proved the absorption ability of bilitranslocase for malvidin-3-O-glucoside and/or quercetin in the rat stomach, as well as in the human vein endothelial and hepatic cell lines (Maestro et al., 2009; Passamonti et al., 2003). Ingestion of flavonoid-rich beverages is acutely caus- ing vasodilation, the bilitranslocase-mediated flavonoids uptake of vascular endothelial cells was regarded as the main cause (Maestro et al., 2009). However, though bilitranslocase is a significant way to absorb anthocyanin at the apical side of stomach and intestine, there is no effective efflux transporters except GLUT 2 (involved

References al. (2013) et Kobayashi al. (2001), Lafay et Deprez (2008), and Gil-Izquierdo al. (2017) et Domínguez-Avila al. (2014) et Tarahovsky with none of MRP 1, MRP 3, MRP 4, SMCT 1, MCT 4, OCTN 1) for them localizing on basal membrane (Fernandes et al., 2014; Passamonti et al., 2009). One cause might be the unavailability of anthocyanins’ metabolism in the gastric mucosa. Therefore, much anthocyanins were retained in the epithelium of digestive tract (up to 60%) or transported back to the lumen through efflux transporters, rather than to penetrate into the blood; they may partially enter into systemic circulation through interacting with lipoproteins in enterocytes (Passamonti et al., 2009). This provides a potential explanation for the lowest bioavailability of anthocyanins among the 6 popular dietary phenolics mentioned above, namely anthocyanins, isoflavones, flavanones, flavonols, flavanols, and phenolic acids. Human OAT 1 and 3 are highly expressed in the basal membrane of human proximal tubular epithelial cells involved in the uptake of endogenous and exogenous organic anions including phenolics and their metabolites. Whilst OAT 4 positions on the apical side of renal proximal tubule cells and transports phenolics therein as well, which may reabsorb phenolic anions from urine and slow

). https://www.proteinatlas.org/ down actual phenolic excretion rate (Hong et al., 2007; Passamonti

Phenolic substrates small molecule Lipophilic and amphipathic catechin, quercetin, daidzein, (genistein, dihydrogenistein, EGC, ECG, EGCG, quercetin-3-O-glucuronide, dihydrodaidzein, quercetin-7-O-glucuronide) phenolic Small molecules/ions (various acids and phenolic acid metabolites: acid, acid, 3-hydroxybenzoic chlorogenic acid, 3,4-dihydroxyphenylpropionic catechin, acid; acid, chlorogenic caffeic dimer/trimer ) proanthocyanidin complexes Phenolic-protein et al., 2009; Volk, 2014; Wang and Sweet, 2013). OATP1A2 and OATP2B1 belong to organic anion transporting polypeptide family and facilitate the accumulation of anionic xenobiotics including phenolics (quercetin) in various cells relying on the mechanism of proton-coupled transport or hydroxyl ion-exchange transport Direction Depends Depends — (Glaeser et al., 2014; Tamai, 2012). Overall, the subgroup of OAT, OATP, OCT, and OCTN are all the members of solute carrier (SLC) 22 gene family playing a major role in the homeostasis of organic ions, mainly function in the kidney (proximal tubule cells) and liver (sinusoidal membrane of hepatocytes). They mediate the uptake of organic cations and anions as the first step of urinary and biliary secretion, respectively (Volk, 2014). More details about distribu- - expres Protein sion level tion, flux direction and expression quantity of different free/active/ facilitated transporters are summarised in Table 6. Beside free diffusion, facilitated diffusion and active transport,

- (continued) the apical endocytosis also contributes to the phenolics uptake of epithelium such as enterocytes and other cells including mac- rophages. Initially, phenolics such as kaempferol, galangin, dios- metin, luteolin, taxifolin, catechins interact with immunoglobulins/ Distribution All the tissues All the tissues All the tissues albumins/lipoproteins in the digestive, extracellular, or intracellular fluids. Then if the complexes were delivered to the specific site of cells (lipid raft on the external leaflet of the membrane), they could enter the cytoplasm through caveolar-/clathrin-dependent endocytosis. More details on endocytosis/exocytosis transport of phenolics are available elsewhere (Blok et al., 1981; Burton and Smith, 1977; Tarahovsky et al., 2014). Transporter Transporter name

2.2.3. Efflux transport of enterocytes

After entering of phenolics into the cytoplasm, some lipophilic Encoding Encoding gene Passive diffusion Passive transport Paracellular Endocytosis/exocytosis

Table 6. Phenolic transporters in human tissues 6. Phenolic transporters Table Atlas” ( online database from “The Human Protein available are level expression about protein information More phenolics could pass through the basal membrane into blood with-

30 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Table 7. Phenolic transporters within human blood-brain barrier Transporter name Location on capillary endothelial cells Orientation Citation MRP 1 Both Endothelium to blood, Faria et al. (2012), Milbury (2009). endothelium to brain MRP 4 Both Endothelium to blood, Milbury (2009), Sier (2015). endothelium to brain MRP 2 Both Endothelium to blood, Faria et al. (2012), Milbury (2009). endothelium to brain MDR 1 Luminal Endothelium to blood Faria et al. (2012) BCRP Luminal Endothelium to blood Faria et al. (2012), Cheng et al. (2012). MCT 1 Both Blood to endothelium, Faria et al. (2012) brain to endothelium MATE 1 — — Geier et al. (2013) SGLT 1 Abluminal Brain to endothelium Faria et al. (2012) OCT 2 Luminal Blood to endothelium Faria et al. (2012) OAT 3 Abluminal Brain to endothelium Faria et al. (2012) OATP1A2 Luminal Blood to endothelium Cheng et al. (2012) OATP2B1 Both Blood to endothelium, Faria et al. (2012), Cheng et al. (2012). Endothelium to brain GLUT 1 Both Blood to endothelium, Faria et al. (2012) endothelium to brain GLUT 4 — — McCall et al. (1997) out metabolism such as A/B-type proanthocyanidin (Appeldoorn porter and facilitates to exclude xenobiotics out of cells (Borst et et al., 2009). While more aglycones and glycosides will be metabo- al., 2000). As the highly expressed absorptive transporters in small lized (or not) to produce phenolic conjugates (e.g., glucuronates and/or large intestinal cell, these efflux transporters prefer to trans- and sulfates), and then further flux into blood capillary or digestive port intracellular phenolic metabolites (organic anions form) into tract. The specific metabolism process in the intestinal cells is dis- the circular system and avoids toxicity caused by phenolics accu- cussed in the next section, but here we focus only on the transport mulation in enterocytes (Borst et al., 2000; Estudante et al., 2013). mechanism. First of all, flux direction of phenolics in the cyto- Similar to the substrates range of MRP 1 and 3, MRP 2 is also an plasm based on the localization of transporters (efflux from the gut anion transporter can actively transport phenolic conjugates (e.g. lumen or endothelial cells into cells or lumen) is considered. While naringenin glucuronides, resveratrol glucuronide and sulfate con- efflux transporters placed in basal membrane, phenolic metabolites jugates) as well as non-conjugated anionic phenolics (e.g. epicat- succeed in being absorbed and entering into systemic circulation. echin) out of the intestinal cells, but the flux direction is from cy- Multidrug resistance-associated proteins 1, 3 and 4 (MRP 1, 3 and toplasm to lumen attributed to its expression on apical membrane 4) are three well-known efflux transporters located on the basal of small and large intestine (Estudante et al., 2013). As a result, ex- membrane and belong to multidrug resistance-associated protein cept for cationic anthocyanins, the actual absorbability of various (MRP) family which is a subgroup of ATP-binding cassette trans- orally ingested phenolics may be suppressed by efflux mechanism

Table 8. Main enzymes in phase I metabolism Category Main Enzymes Common Reactions Products Oxidation Alcohol oxidases; Aldehyde oxidases; Aromatic C-oxidation; Aliphatic Phenols; Alcohols; Ketones; Xanthine oxidases; Monoamine C-oxidation; N- and S-oxidation. Aldehydes; Epoxides; oxidases; Flavin-containing Epoxidation; Dehydrogenation; Ketenes; Acids; N- and monooxygenases; Cytochrome P450s. N-, O- and S-dealkylations. S-oxides; Amines; Thiols. Hydrolysis Carboxylesterases; Peptidases; Hydrolysis of esters, amides, epoxides. Alcohols; Acids; Amines. Epoxide hydrolases; Cholinesterases; Paraoxonases. Reduction Alcohol Dehydrogenases; Carbonyl Reduction of azo, nitro groups, carbonyl Groups, Phenols; Alcohols; Reductases; NADPH-quinone sulfoxides and N-oxides, quinones; Reductive Ketones; Sulfides; Acids; oxidoreductases; NADPH- Cleavage of Heteroaromatic Compounds; Disulfide Amines; Thiols. cytochrome P450 reductases. reduction and reductive dehalogenation.

Adapted from Timbrell and Marrs (2009), Smart and Hodgson (2018), Shimada et al. (2006), and Hodgson et al. (2001).

Journal of Food Bioactives | www.isnff-jfb.com 31 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Figure 2. Cytochrome P450 catalytic process.

32 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Table 9. Products of CYP-450s-catalyzed oxidation Substrate Enzymes Product(s) Enzyme source References Galangin CYP2C9*, CYP1A1,CYP1A2 Kaempferol Human liver microsomes Otake and Walle (2002b) Kaempferide CYP1A2*, CYP1A1, CYP2C9 Kaempferol Human liver microsomes Kaempferol CYP1A1 Quercetin Hamster high-expressed Silva et al. (1997) CYP-450s ovary cell Chrysin CYP1A1, CYP1A2 Apigenin (major), scutellarein Aroclor 1254-induced Nielsen et al. and isoscutellarein rat liver microsomes (1998), Gradolatto et al. (2004). Naringenin CYP1A Eriodictyol Aroclor 1255-induced rat liver microsomes Hesperetin CYP1A Eriodictyol Aroclor 1256-induced rat liver microsomes Apigenin CYP1A Luteolin Aroclor 1257-induced rat liver microsomes Tamarixetin CYP1A Quercetin Aroclor 1258-induced rat liver microsomes α-Naphthoflavone CYP-450c, epoxide hydrolase 7,8-Dihydro-7,8-dihydroxy- Rat liver microsomes. Andries et al. α-naphthoflavone (1990), Vyas 5,6-Dihydro-5,6-dihydroxy- et al. (1983). α-naphthoflavone 5,6-Oxide-α-naphthoflavone 6-Hydroxy-α-naphthoflavone 9-Hydroxy-α-naphthoflavone Tangeretin CYP1A Demethyl tangeretin or Rat and human liver Canivenc-Lavier multi-demethyl tangeretin microsomes. et al. (1993) β-Naphthoflavone Unknown CYP-450s 8-Hydroxy-β-naphthoflavone Rat liver microsomes. Vyas et al. (1983) β-Naphthoflavone CYP-450c, epoxide hydrolase Trans-7,8-dihydro-7,8- Rat liver microsomes. dihydroxy-β-naphthoflavone Trans-5,6-dihydro-5,6- dihydroxy-β-naphthoflavone 5-Hydroxy-β-naphthoflavone of multidrug resistance-associated protein 2 (MRP 2) (Walgren et body, which should have a better absorbability due to its high al., 2000a; Walle, 2004). Besides, several other transporters such membrane permeability; a similar result was also found in rats. as multidrug resistance 1 (MDR 1) and breast cancer resistance Considering the previous data of Walle et al. (1999; 2001) in Caco- protein (BCRP) present an overlapping function and even boarder 2 study of chrysin absorption, it may be concluded that efflux of substrate specificity including hydrophobic flavonoids and other metabolites back into the lumen is one of the important causes for cationic or amphipathic xenobiotics, which contributes to the ex- extremely low oral bioavailability of chrysin. cretion of these substrates in the renal tubular luminal membrane So far, in addition of passive diffusion, transcellular transport, (Estudante et al., 2013; Volk, 2014). By the way, O’Leary et al. and Endocytosis/exocytosis, 25 transporters are known to signifi- (2003) found that MDR 1 was not the main efflux transporter for cantly affect bioavailability including absorption, translocation, quercetin conjugates but MRP 2 was proven to be the one. While and disposal of dietary phenolics which may be responsible for BCRP is highly overlapping in substrate specificities with MRP- further phenolic bioactivity in specific tissues such as penetration 2 and MDR 1 and prone to exclude anionic compounds such as of phenolics into the blood-brain barrier (Table 7). phenolic conjugates (e.g., quercetin, naringenin, resveratrol conjugates) as well as non-conjugated phenolics (e.g., quercetin, genistein, daidzein, and coumestrol). Furthermore, MCT 4 was most 3. In vivo Metabolism recently proposed to be an efflux transporter positioning on the basal side of enterocytes and exclude phenolic acids in the same In the human body, phenolics are one class of xenobiotic whose direction of MRP 1, they facilitate the entrance of phenolics into molecular structures and biochemical properties are modified by the blood (Ziegler et al., 2016). These transporters are moderately specialized enzymatic systems and further conjugated with charged or highly expressed at the apical membrane of enterocytes thereby species after absorption, which aims to polarize absorbed xenobiot- limiting the intestinal absorption of many important xenobiotics ic and enable them to be transported and excreted in regular routine including dietary phenolics (Estudante et al., 2013). As an exam- instead of uncontrollably accumulating in tissues or freely diffusing ple, the relatively lipid-soluble chrysin was estimated to have an across membranes. These associated intracorporal biotransforma- actual bioavailability of only 0.003–0.02% in the normal human tion and transportation pathways after absorption of phenolics are

Journal of Food Bioactives | www.isnff-jfb.com 33 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

indeed in vivo phenolic metabolism. The classical phenolics metabolism contains three stages: phase I (modification phase), phase

(μl/ II (conjugation phase) and phase III (excretion phase) (Xu et al., m

/K 2005). For every phase, the enzyme involved is complex and not entirely understood. Briefly, the phase I metabolism of xenobiotics max 1.9 10.2 V min/mg) contains a set of structural modification including thiolation, hydroxylation, amination, N-/O-dealkylation, or carboxylation conducted by certain phase I enzymes (Table 8). For phenolic phase I metabolism, hydroxylation of hydrocarbon sites especially the CYP1A1 (pmol/ aromatic carbon catalyzed by a large group of hemoprotein mo- max 12.4 10.8 mg/min) V nooxygenases: the cytochromes P450s (CYP-450s) is the most widely studied route (Fig. 2) (De Montellano, 2005; Guengerich, 2007). Recently, cytochrome P450 3A was found to account for

(μM) the majority of total cytochromes P450 superfamily extensively ex- m 6.4 1.1 K pressed in the human tissues: liver ( 35%) and gut ( 82%), thus acting as the main enzymes involved in the oxidative reaction, followed by CYP2C (one reported 14%∼ in liver and ∼16% in gut, (μl/

m another one reported 30–40% in liver) and CYP1A, CYP2A, CY-

/K P2D, CYP2E, CYP2J and CYP2D∼ are also abundantly expressed

max (Domínguez-Avila et al., 2017; Galetin et al., 2010; Heim et al., 5.1 58 min/mg) V 2002; Kadlubar and Kadlubar, 2010). As reported earlier, hydroxylation of flavonoids is mainly catalyzed by CYP1A isozymes and demethylation by other CYP-450s (except CYP1A and CYP3A) CYP2C9

(pmol/ subgroup (e.g., CYP2C) (Table 9). However, some exceptions such

max as chrysin, eriodictyol, taxifolin, luteolin, quercetin, myricetin, fi- 41 23 V mg/min) Recombinant CYP-450s Recombinant setin, morin or isorhamnetin exist that cannot be found to be oxidized by the normal CYP-450s system (Nielsen et al., 1998; Otake and Walle, 2002b; Silva et al., 1997). The oxidation catalyzed by 8.1 0.4 Km (μM) CYP-450s prefers to happen on both A-ring (hydrogenation of C-5, 6 or C-7, 8; hydroxylation of C-5, 6 or 7, 8; epoxidation of C-5, 6) and B-ring (hydroxylation and demethylation of C-3′ and/or 4′

/K (μl/ until form a 3′,4′-dihydroxyl structure) (Andries et al., 1990). For

max example, hydroxylation of apigenin dominantly happens on C-3′, 21 32 min/mg) V followed by C-5 and 7 positions (Table 9) (Gradolatto et al., 2004). This hydroxylation process may enhance the antioxidant activity of phenolics, and the enhancing extent depends on the hydroxyla-

(pmol/ tion ability of the site and the degree of hydroxylation. Simultane- CYP1A2

max ously, the abundance of hydroxyl groups (≥2) on the B-ring may 89 81 mg/min) V prevent further hydroxylation of flavonoids such as quercetin for which no phase I hydroxylated metabolites were detected. Besides, some other factors may affect the phase I metabolism carried by (μM)

m CYP-450s. Polarity dominates the metabolism rate of hydroxyla- 4.3 2.5 K tion, the hydrophobic one (with a less free hydroxyl group) was metabolized faster (Nielsen et al., 1998). Demethylation selectively

(μl/ occurs in the B-ring in CYP-1A-mediated monooxygenase system m

/K when the methoxy group is positioned at C-4′ but not at the C-3′ (more stable), whereas C-ring structure takes minor and no effect max 10.8 ± 1.9 13.6 ± 1.1 V min/mg) on hydroxylation and demethylation, respectively (Nielsen et al., 1998). On the other side, hydroxyl group on B-ring could be methylated by catechol-O-methyltransferase (COMT) in phase II metabolism, thus it may form a circulation between 4′-O-methylation (pmol/ and 4′-O-demethylation until: 1) transforming to be 3′-O-methyl on max 181 ± 32 129 ± 11 mg/min) V catechol group and exclude out of cell; 2) sulfation/glucuronidation of 4′-O-methyl aglycones and produce methylquercetin sulfates/ .

Human liver microsomes Human liver glucuronides and excluded out of cell; 3) directly excluded out of cell (Nielsen et al., 1998; O’Leary et al., 2003). Overall, CYP-450s (μM)

m involved in the metabolism of flavonoids exhibit stereo-selectivity 17.8 ± 3.5 9.5 ± 0.4 K toward the flavonoid substrates. Apart from the methylation mentioned above, there are several other phase II metabolic reactions such as glucuronidation, sulfation, acetylation, amino acid conjugation, and glutathione conjugation. Amongst them, glucuronidation and sulfation are prevalently found in phenolic metabolism catalyzed by uridine 5′-diphospho- Kaempferide Galangin Substrate

Table 10. Kinetic parameters of CYP-450s-catalyzed oxidation of CYP-450s-catalyzed parameters 10. Kinetic Table al. (2002a) et Otake from Adapted glucuronosyltransferases (UDP-glucuronosyltransferases or UGTs)

34 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Table 11. Kinetic parameters of glucuronidation and sulfation of galangin K (μM) V (pmol/mg of protein/min) V /K (μl/min/mg) Enzyme Source m max max m Peak 1 Peak 2 Peak 1 Peak 2 Peak 1 Peak 2 Recombinant UGTs Human liver microsomes 3.6 ± 0.7 221 ± 31 1,521 ± 252 34,333 ± 2,167 427 ± 26 155 ± 30 UGT1A9 1.1 31.8 721 3,594 655 113 UGT1A1 N.D. 6.3 N.D. 388 N.D. 62.1 UGT2B15 N.D. 15.7 N.D. 538 N.D. 34.3 Recombinant SULTs SULT1A1 0.21 3,270 15,572 SULT1A3 37.1 822 22.2 SULT1E1 1.13 948 839

Adapted from Otake et al. (2002a). and sulfotransferases (SULTs). The same as that of methylation, the tabolites, the glucuronic conjugates of EGCG such as EGCG-3″-O- reactive sites on phenolics are hydroxyl groups. The glycine con- glucuronide and EGCG-3′-O-glucuronide increase the DPPH scav- jugation of hydroxybenzoic acid or benzoic acid is also a common enging activity compared to that of the EGCG aglycone (Monagas phase II reaction catalyzed by benzoyl CoA which finally produces et al., 2010). Based on these studies, there is no doubt that dietary the hippuric acid or hydroxyhippuric acid (Toromanović et al., phenolics have extremely low bioavailability and detoxification 2008). Several phase II phenolic metabolites are shown in Table 9. metabolism which results in an uncertainty of their physiological These conjugations caused by UGTs, SULTs, and COMT may re- effects, however, they could still play a vital role on health. Morand sult in the alteration of phenolic bioactive properties; some of these et al. (1998) stated that a diet containing 0.2% quercetin enhances metabolites lose their activities. For example, glucuronidation of about 60% antioxidant ability of rat plasma compared with that of isoflavonoids (e.g., daidzein and genistein) exert lower biological the control group. Other in vivo antioxidant activity tests of healthy activities including estrogen receptor binding capacity and natural human were demonstrated in a more recent review (Martins et al., killer cell activation ability (Wu et al., 2011). The serum metabol- 2016). ic mixture of fisetin (fisetin sulfates/glucuronides) showed lower Generally, compared with phase II metabolism, phase I metabo- ability than native fisetin in the inhibition of hemolysis induced by lism pathway of phenolics mediated by CYPs is relatively less en- AAPH (2,2′-azobis (2-amidinopropane hydrochloride)) (Shia et al., countered (may result from the low reaction rate of CYPs; refer to 2008). A lower value was also shown by glucuronidates/sulfates of Tables 10–12) (Chen et al., 2014). Phase I metabolism is not such flavonols (e.g., quercetin) in delaying the copper-induced lipopro- a necessary prerequisite for phase II metabolism of xenobiotics al- tein oxidation (Morand et al., 1998). The resveratrol sulfates dis- though a contribution from CYP-mediated oxidation cannot be en- played low antiproliferative/antitumor activity, and its correspond- tirely ignored in phenolic metabolism. Phenolics could first carry ing sulfates/glucuronides partially lost their inhibitory activity on through phase I and then phase II metabolism or directly proceed COX-1 and 2 compared to the parent resveratrol (Calamini et al., to phase II metabolism. Meanwhile, phase III stage of phenolics 2010; Hoshino et al., 2010; Miksits et al., 2009; Rotches-Ribalta is the phenolic excretion process which is involved with various et al., 2012a). Furthermore, 3-O-glucuronidation and 3′-O-sulfation efflux transporters in the kidney, liver, and intestine (refer toTable of quercetin diminished the PGE2 inhibitory activity of the original 6) is not described here. quercetin in cell test. The LTB4 inhibiting activity of quercetin was also lost due to the 3′- and 3-conjugation of quercetin (3′-O-methylquercetin and quercetin-3′-O-sulfate, quercetin-3-O-glucuronide 3.1. Phase I and phase II enzyme distribution and 3′-O-methylquercetin-3-O-glucuronide) (Loke et al., 2008). Whereas some phenolics contrarily obtain higher bioactivity as me- In the human body, intestine and liver are the two most impor-

Table 12. Kinetic parameters of COMT-catalyzed O-methylation Hamster kidney cytosol Recombinant COMT from Porcine liver

Rate (pmol/mg/min) Rate (pmol/mg/min) Km (μM) Vmax (pmol/mg/min) Vmax/Km (μl/min/mg) Quercetin 109 ± 11 9,100 ± 47 6.1 14,870 2,438 Fisetin 119 ± 8 13,100 ± 101 4.8 17,700 3,687 2-Hydroxyestradiol 32 ± 3 2,206 ± 21 16.2 4,123 255 4-Hydroxyestradiol 9 ± 2 414 ± 11 23.4 2,560 109 Epinephrine ND 16 ± 2 1,036 2,754 2.66 Norepinephrine ND 9 ± 2 1,149 1,990 1.73 Dopamine ND 31 ± 3 1,018 5,182 5.09

Adapted from Zhu et al. (1994).

Journal of Food Bioactives | www.isnff-jfb.com 35 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Figure 3. Metabolism of quecetin monoglycoside. tant tissues for phase I and phase II metabolism of phenolic the small intestine rather than the liver due to a higher expression compounds; other tissues including muscle and brain are also level of phenol SULTs in the intestine. This difference was con- commonly involved and investigated. In the small intestine of hu- firmed in a later study (van der Woude et al., 2004). For phenolic mans, the expressed total amount of CYP-450s is less than 1% glycination, the synthesis site of hippuric acid/hydroxyhippuric of that in hepatic tissues. COMT and UGTs are extensively ex- acid almost entirely occurs in the human liver (Toromanović et pressed in various organs mentioned (Galetin et al., 2010; Merello al., 2008). et al., 1994). Similar to the distribution of CYP-450s, the highest expression of COMT is present in liver, followed by gastrointesti- 3.2. Phase II metabolism in enterocytes nal tract, kidneys, and other tissues (O’Leary et al., 2003). In contrast, the expression level of the two main phenol SULTs (SULT 1A1 and SULT 1A3) is the highest in the small intestine, followed After being absorbed phenolics enter into the intestinal and he- by liver, stomach, and colon. For UGTs, UGT 1 and 2 are the patic cells; original phenolic glycosides may be hydrolyzed two major subgroups in catalyzing phenolic glucuronidation ex- into aglycones by an intracellular β-glucosidase, called broad- pressed on either liver, gastrointestinal tract, kidney or other or- specificity cytosolic β-glucosidase which is rich in mammalian gans (Fisher et al., 2001; Rowland et al., 2013). More distribution liver, kidney and small intestine (Day et al., 1998; Hays et al., information has been summarized in Table 10. In normal living 1996). However, the rate and extent of deglycosylation are still cells, the CYP-450s, UGTs, and SULTs are expressed on the cy- variable due to the distinct structure of the phenolic aglycones tosolic face of the endoplasmic reticulum (ER), the luminal face and the position/nature of the sugar substitutions. Specifically, of ER, and cytosol, respectively (Galetin et al., 2010; Wu et al., quercetin-4′-glucoside, naringenin-7-glucoside, apigenin-7-glu- 2011). COMT was reported to be the highest expression in liver coside, genistein-7-glucoside, and daidzein-7-glucoside can be and kidney, which could be divided into cytosolic soluble COMT rapidly deglycosylated by both the small intestine and the liver (S-COMT) and rough endoplasmic reticulum membrane-bound β-glucosidase extracts. Herein, genistein-7-glucoside has a higher COMT (MB-COMT). The former is the predominant form in the affinity for β-glucosidase than quercetin-4′-glucoside thus the cells responsible for xenobiotic methylation (Crespy et al., 1999; former shows a higher deglycosylation rate, whereas some other Nissinen et al., 1988). Among rat tissues, Donovan et al. (2001) glycosides such as quercetin-3,4′-diglucoside, quercetin-3-gluco- concluded that liver was primarily responsible for sulfation and side, kaempferol-3-glucoside, quercetin-3-rhamnoglucoside, and methylation of flavonoids and small intestine was the organ in naringenin-7-rhamnoglucoside prefer to remain unchanged (Day which mainly glucuronidation and methylation of flavonoids took et al., 1998). This intracellular reaction is regarded as a vital way place. However, in humans, sulfation should mainly happen in to expose hydroxyl group of xenobiotics for further conjugation

36 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds -nitrophenol and p -nitrophenol Substrates benzylic phenols, naphtols, phenolics (monocyclic Various dopamine, hydroxylamines, alcohols, amines, drugs aromatic genistein,), naringenin, iodothyronines, opioids and fulvestrant), raloxifene, endoxifen, (afimoxifene, naloxone) pentazocine, norbuprenorphine, (buprenorphine, opioids (buprenorphine, hydroxylamines, Aromatic naloxone) pentazocine, norbuprenorphine, molecules, and monocyclic aromatic catechols, Norepinephrine, dopamine, demethoxycurcumin, phenolics (catecholamines, naloxone) opioids (pentazocine, vanillin), curcumin, — and hormones, phenolics (1-naphtol Thyroid bisdemethoxycurcumin) curcumin, 4-nitrophenol, and N-hydroxy-2-acetylaminofluoren 4-Nitrophenol chlorinated hydroxyl ethanol, 5-Hydroxymethylfurfural, hormones bile acids, and thyroid biphenyls, bisdemethoxycurcumin, curcumin, Phenolics (demethoxycurcumin, apigenin, chrysin, daidzein, (genistein, estrogens catechol 1-naphthol, afimoxifene, epirubicin, drugs (doxorubicin, and 6,4′-dihydroxyflavone)), naloxone) opioids (pentazocine, and fulvestrant), raloxifene, endoxifen, pregnenolon, iodothyronines, (17 β -estradiol), Estrogen demethoxycurcumin, p -nitrophenol phenolics (1-naphtol, genistein), naringenin, bisdemethoxycurcumin, curcumin, naloxone) opioids (pentazocine, 4-hydroxytamoxifen, androsterone, epiandrosterone, (dehydroepiandrosterone, Androgens buprenorphine) E2), opioids (pentazocine, testosterone, dehydroepiandrosterone Cholesterol, Brain trace trace trace trace — none none low trace low none Muscle low low none low — none none low none none moderate Kidney moderate low moderate low moderate moderate none low none low none Liver high low none low moderate none none moderate moderate high low Expression level (RNA and Protein expression mixed) expression (RNA and Protein level Expression Gastrointestinal tract Gastrointestinal high high high high high none trace moderate moderate moderate high Isoforms SULT1A2 SULT1A3 SULT1A4 SULT1B1 SULT1C2 SULT1C3 SULT1C4 SULT1E1 SULT2A1 SULT2B1 SULT1A1 - En zyme SULTs Table 13. Phase II enzymes distribution and expression level in recently no drug-administrated human body no drug-administrated recently in level expression and distribution 13. Phase II enzymes Table

Journal of Food Bioactives | www.isnff-jfb.com 37 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. -pregnanes), hyodeoxycholic hyodeoxycholic α -pregnanes), - (continued) acid, NSAIDs (fenoprofen, ketoprofen, naproxen), and opioids naproxen), ketoprofen, (fenoprofen, acid, NSAIDs acid, zidovudine, valproic morphine, naloxone), (codeine, epirubicin, gemfibrozil, chloramphenicol, carbamazepine, Substrates raloxifene, ethynylestradiol, etoposide, Drugs (bilirubin, estradiol, acid, retinoic of irinotecan)), metabolite SN-38 (active buprenorphine, phenolics complex paracetamol), buprenorphine, opioid (naltrexone, acids, amines, phenolics carboxylic or aromatic Aliphatic opioids, anthraquinones), 7-hydroxycoumarins, (flavonoids, drugs (telmisartan) estrogens), (2-hydroxycatechol estrone steroids plant progestins, amines, androgens, Tertiary trifluoperazine) drugs (lamotrigine, olanzapine, (sapogenins), 1-hydroxypyrene 4-methylumbelliferone, SN-38, scopoletin, and primary amines Simple phenolics (4-nitrophenol) ) drugs (paracetamol (5-hydroxytryptamine), and coumarins α )pyrenes, Phenols, benzo( primary amines, and secondary estrogens, Catechol coumarins, phenolics (nitrophenol, retinoids, sapogenins, and opioids anthraquinones), flavonoids, arylamines, N-hydroxy- acids, amines (N-hydroxy Carboxylic anthraquinones), phenolics (flavonoids, complex naphthylamine), acid, frusemide, mycophenolic drugs (paracetamol, steroids, sulfinpyrazone) retigabine, raloxifene, propofol, phenylbutazone, retinoids, acids, fatty steroids, bile acids, Phenolics (flavonoids), and diflunisal) furosemide, and other drugs (ciprofibrate, coumarins phenolics, alcohols, aliphatic acids, monoterpenoid, Carboxylic acid) Bile acids (hyodeoxycholic androsterone) (androstanediol, acid, steroids Hyodeoxycholic estrogens, catechol acids, azido deoxythymidine, Carboxylic 3 (3 α -hydroxyandrogens, Androgens Brain none none Existence (no amount data) Existence (no amount data) Existence (no amount data) none none none moderate moderate — none trace Muscle — — — — — none none none none none trace trace trace Kidney low none none — high none none high none none moderate high high Liver moderate moderate moderate low moderate none none low none none moderate high high Expression level (RNA and Protein expression mixed) expression (RNA and Protein level Expression Gastrointestinal tract Gastrointestinal low moderate low moderate moderate low trace high none high low high low Isoforms UGT1A3 UGT1A4 UGT1A5 UGT1A6 UGT1A7 UGT1A8 UGT1A9 UGT1A10 UGT2A1 UGT2A3 UGT2B4 UGT2B7 UGT1A1 - En zyme UGTs Table 13. Phase II enzymes distribution and expression level in recently no drug-administrated human body no drug-administrated recently in level expression and distribution 13. Phase II enzymes Table

38 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds -pregnanes), estrogen (oestriol) estrogen α -pregnanes), - (continued) Catechol amines (dopamine, salsolinol, tetrahydropapaveroline, amines (dopamine, salsolinol, tetrahydropapaveroline, Catechol various estrogens, catechol norepinephrine) steroids drugs, plant phenolics, various Phenolics (flavonoids), estrogens, androgens (testosterone, (testosterone, androgens estrogens, Phenolics (flavonoids), drugs (lorazepam, androstanediol), dihydrotestosterone, ) sipoglitazar temazapam, oxazepam, steroids and the endogenous eugenol, 4-Methylumbelliferone, dihydrotestosterone) androsterone, androstanediol, (testosterone, androsterone) androstanediol, (testosterone, Androgens Substrates androsterone), androstanediol, (testosterone, Steroids and nicotine) amines (cotinine tertiary 3 (3 α -hydroxyandrogens, Androgens moderate — — none Brain Existence (no amount data) none low trace trace none Muscle none none high Existence Existence (no amount data) — none Kidney none none . moderate low none high Liver high moderate Expression level (RNA and Protein expression mixed) expression (RNA and Protein level Expression Collins et al. (1973) , and Collins et moderate high high high Gastrointestinal tract Gastrointestinal none low UGT2B17 UGT2B28 UGT2B15 Isoforms UGT2B10 UGT2B11 Court et al. (2012), Rowland et al. (2013), Jancova et al. (2010), Cheng et al. (1999), Margaillan et al. (2015), Wong et al. (2009), Finel et al. (2005), King et al. (1999), Mostaghel et al. (2016), King et al. (2000), Teubner Teubner (2000), al. et King (2016), al. et Mostaghel (1999), al. et King (2005), al. et Finel (2009), al. et Wong (2015), al. et Margaillan (1999), al. et Cheng (2010), al. et Jancova (2013), al. et Rowland (2012), al. et Court - COMT En zyme Table 13. Phase II enzymes distribution and expression level in recently no drug-administrated human body no drug-administrated recently in level expression and distribution 13. Phase II enzymes Table from Cited et al. (2007), Cheng et al. (1998), Cheng et al. (1999), Barbier et al. (2000), Knights et al. (2013), Chimalakonda et al. (2011), Riches et al. (2009), Ghosh et al. (2013), Sakamoto et al. (2015), Lu Guidry et al. (2017), et al. (2011), (2009), (2013), Riches Ghosh Sakamoto et al. (2013), Chimalakonda et al. al. (2000), (2007), (1998), (1999), Knights Cheng Barbier et et al. (2015) al. (2017), Hui et et Kurogi

Journal of Food Bioactives | www.isnff-jfb.com 39 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Figure 4. Metabolism of apigenin-C/O-glycosides. in phase II metabolism. oxidized or/and conjugated in the gastrointestinal cells, thus easy After deglycosylation, together with original phenolic glyco- to undergo ionization. A considerable portion of these phenolic sides and aglycones, a part of aglycones hydrolyzed from glyco- ions would further be conjugated and excluded from enterocytes sides is transported into the blood or/and lymph, whilst others are back to intestinal lumen and undergo enteroenteric recirculation

Figure 5. Metabolism of resveratrol and resveratrol glycoside.

40 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds Rectum 7.0–7.5 Large intestine Large Colon 5.5–7.0 12 –10 8 10 Cecum 5.9–6.4 4–72 hours (36 hours) 4–72 hours Verrucomicrobia, Bacteroidetes, Firmicutes, Spirochaetes, Actinobacteria, Proteobacteria, Fusobacteria, Tenericutes, Cyanobacteria, Deinococcus- Acidobacteria, Lentisphaerae, TM7, Thermus, SR1, Synergistetes, Gemmatimonadetes, Nitrospira, Thermotogae, Deferribacteres OD1, Aquificae, ∼ 21 amount: phylum Total (1), Propionibacterium (1), Aquifex Thermotoga (2), Ethanoligenens (2), Listeria (2), Bradyrhizobium (1), (1), Cellulosilyticum (1), Staphylococcus (2), Vibrio (4), Burkholderia (3), Deinococcus (1), (3), Shewanella Neisseria (1), Nitrobacter (1), Mycoplasma (1), Proteobacterium Finegoldia (1), (1), Exiguobacterium (1), Bacillus Yersinia (1), Mobiluncus Leuconostoc Acinetobacter (3) Achromobacter (1), Paenibacillus (1), Catonella (2), Edwardsiella (1), Pediococcus (1), Moraxella (1), Filifactor (3), Abiotrophia (1), Oenococcus (1), (1), Rahnella Sodalis Brachyspira (1), (1), Methanosphaera Methanobrevibacter (4), Collinsella Atopobium (11), Bifidobacterium (3), Eggerthella (4), Olsenella (1), Slackia (2), (1), Parabacteroides (41), Odoribacter Bacteroides (1), (3), Paraprevotella (3), Porphyromonas (7), (3), Capnocytophaga (21), Alistipes Prevotella (1), (25), Weissella (4), Lactobacillus Enterococcus (36), Clostridium (1), Streptococcus Lactococcus (2), (2), Parvimonas (20), Anaerococcus 8 –10 7 Illeum 6.5–7.5 10 7 –10 5 Jejunum 6.5–7.5 10 Small intestine 5 –10 3 10 Duodenum 5.5–7.0 3–5 hours Bacteroidetes, Proteobacteria, Firmicutes, Firmicutes, Proteobacteria, Bacteroidetes, Verrucomicrobia, Fusobacteria, Actinobacteria, Deinococcus-Thermus, Cyanobacteria, TM7, Tenericutes, SR1, Spirochaetes, Chloroflexi, Thermotogae, Lentisphaerae, OP10, Synergistetes, Acidobacteria, Gemmatimonadetes, Planctomycetes, OD1, Aquificae Deferribacteres, ∼ 23 amount: phylum Total (2), (1), Thermus Deinococcus Aquifex (1), Bifidobacterium (1), Trophetyma Leifsonia (1), Thermobifida (1), Propionibacterium (1), Corynebacterium (2), Frankia Streptomyces (4), (1), Mycobacterium (4), Norcadia (1), Borrelia (9), Leptospira Streptococcus (2), Dehalococcoides (2), Treponema (1), Prochlorococcus (2), Gloeobacter (1), (1), Moorella (1), Symbiobacterium (12), (1), Mycoplasma Desulfitobacerium (1), Lactococcus (5), Enterococcus Lactobacillus (2), Bacillus (3), Acidobacerium (1), Listeria (1), (2), Syntrophus (1), Desulfovibrio (1), (1), Anaeromyxobacter Bdelloviobrio (1), Sulfurimonas (2), Pelobacer Geobacter (1), Helicobacter (1), Wolinella Campylobacer (1), Anaplasma (2), Rickettsia (2), Erythrobacter (2), Ehrlichia Caulobacer (1), (5), Wolbachia (1), Rhizobium (1), Sphingopyxis Gluconobacer (1), Rhodopseudomonas (1), Sinorhizobium (1), Brucella (5), (1), Bradyrhizobium 3 Stomach 1.0–4.0 0.5–5 hours Proteobacteria, Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, TM7, Fusobacteria, Deferribacteres, Acidobacteria, Chloroflexi, Cyanobacteria, Deinococcus- Thermus phylum Total ∼ 15 amount: (5), Eubacterium (1), Deinococcus (1), Bergeyella Chryseobacterium (1), Capnocytophaga (1), Cytophagales (1), Prevotella pallens (20), Porphyromonas (2), (2), Tannerella Fusobacterium (5), Leptotrichia (5), Streptococcus (12), Granulicatella (1), Abiotrophia (1), Enterococcus (1), Lactobacillus (2), Weissella (1), Gemella (2), Veillonella < 10 Esophagus 4.0–7.0 5–10 seconds Proteobacteria, Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Fusobacteria, TM7, Spirochaetes, SR1, Tenericutes, Synergistetes, GN02, Chloroflexi, Cyanobacteria, Armatimonadetes, Thermotogae, TM6, WPS-2, Chlamydiae, WS6, Verrucomicrobia, Gemmatimonadetes, Acidobacteria phylum Total ∼ 29 amount: (12), Streptococcus (17), Prevotella (3), Veillonella (2), Granulicatella (5), Lactobacillus Gemella (3), Bulleidia (1), Paenibacillus (1), Eubacterium (1), Mogibacterium (1), (1), Filifactor Peptostreptococcus (1), Megasphaera (1), Micronuciformis (1), Selenomonas (1), (1), Centipeda (7), Clostridiales (2), Rothia Atopobium (4), (1), Actinomyces Comamonas (1), — 9 –10 7 Oral cavity Oral 7.0 10 0.5–1 min Proteobacteria, Firmicutes, Actinobacteria, Actinobacteria, Firmicutes, Proteobacteria, TM7, Bacteroidetes, Fusobacteria, SR1, Spirochaetes, Chloroflexi, Chlamydiae, Deferribacteres, Tenericutes, Synergistetes, Chlorobi, Cyanobacteria, Acidobacteria, Verrucomicrobia, Deinococcus-Thermus, Elusimicrobia WS6, GN02, WPS-2, ∼ 29 amount: phylum Total (1), (49), Deinococcus Streptococcus (4), (1), Enterococcus Lactococcus (1), (2), Abiotrophia Granulicatella (1), (1), Alloiococcus Dolosigranulum (19), Gemella (4), Paenibacillus Lactobacillus (1), Staphylococcus (2), Bacillus (4), Listeria (1), Bulleidia (4), Erysipelothrix class sp. (1), Mollicutes Solobacterium (9), (9), Eubacterium (1), Mycoplasma (2), (5), Peptostreptococcus Mogibacterium (3), Finegoldia (1), Parvimonas Filifactor (6), (2), Peptoniphilus (1), Anaerococcus sp. (6), Pseudoramibacter order Clostridiales (1), Johnsonella (2), Butyrivibrio Catonella (1), Oribacterium (3), Shuttleworthia (2), Selemonomas (22), (5), Peptococcus Veillonella (3), (1), Mitsuokella Centipeda (2), (1), Megasphaera (5), Anaeroglobus (24), Mobiluncus (5), Actinomyces Dialister (1), (1), Actinobaculum Arcanobacterium Phyla detected detected Phyla in different individuals Partially named Genera detected in different individuals of (The amount named species) pH Microbiota density (cells/ Microbiota ml or g contents) Stay time of food residue food time of Stay Bacteria Bacteria diversity Table 14. The fundamental physicochemical condition and bacterial diversity in different segments of the digestive tract of the digestive segments in different diversity and bacterial condition physicochemical 14. The fundamental Table

Journal of Food Bioactives | www.isnff-jfb.com 41 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. Rectum Large intestine Large Colon Cecum (6), Pelotomaculum (4), Eubacterium Peptoniphilus (1), (1), Mobiluncus Lawsonia (1), Acetivibrio (1), Epulopiscium Anaerostipes Caulobacter (7), Thermoanaerobacterium (2), Ruminococcus (1), Blautia (2), Butyrivibrio Coprococcus (1), (3), Oscillibacter (2), Roseburia (3), Dorea (2), Pseudoflavonifractor Peptostreptococcus (3), (1), Faecalibacterium (1), Anaerotruncus (2), Holdemania (1), Solobacterium Coprobacillus (3), (2), Acidaminococcus (1), Turicibacter (1), Dialister (1), Centipeda Phascolarctobacterium (1), Selenomonas (3), Mitsuokella (1), Megasphaera (7), Acidovorax (5), Fusobacterium (4), Veillonella (2), Parasutterella (1), Comamonas Oxalobacter (3), (1), Bilophila Desulfovibrio (1), Sutterella (1), Aeromonas (5), Helicobacter Campylobacter (1), Grimontia (1), Gardnerella (4), Succinatimonas (1), (1), Anaerofustis (1), Subdoligranulum (1), (1), Ralstonia (1), Xenorhabdus Anaerobaculum (3), Citrobacter (1), Oribacterium Shuttleworthia (9), Escherichia (2), Enterobacter (4), Cronobacter (4), (2), Providencia (4), Proteus (10), Klebsiella (5), Actinobacillus (3), Salmonella (2), Shigella (1), Haemophilus (8), (3), Basfia Aggregatibacter (2), (1), Mannheimia Pasteurella Histophilus (1), Akkermansia (1), Pyramidobacter Treponema (1), Gemella Mycobacterium (1), Victivallis (4), (1), Corynebacterium (2), Laribacter (1), (1), Cardiobacterium Granulicatella (1), (1), Eikenella (2), Marvinbryantia Leptotrichia (1), Arcobacter (1), Bartonella Dysgonomonas (2) (1), Brucella Pelobacter (1), Ureaplasma ∼ 400 amount: genera Total ∼ 400–500 species amount: Total Illeum Jejunum Small intestine Duodenum Burkholderia (3), Ralstonia (7), Bordetella (7), Bordetella Burkholderia (3), Ralstonia (3), (1), Xanthomonas (3), Chromobacterium (1), Methylococcus (1), Nitrosococcus Xylella (1), Legionella Thiomicrospira (1), Coxiella (2), Hahella (1), Psychrobacter (1), Francisella (1), Pseudomonas (1), Chromohalobacter (2), (1), Shewanella (4), Saccharophagus (1), (1), Photobacerium Vibrio (4), Colwellia (1), Yersinia (1), Francisella Pectobacterium (1), Salmonella (1), Candidatus (2), Buchnera (4), Escherichia (1), Mannheimia (2), Shigella (1), (1), Photohabdus (1), Pasteurella (1), Desulfovibrio Idiomarina (1), Lawsonia (2), (1), Wolbacchia (2), Campylobacter (2), (1), Jannaschia Slicibacter Zymomonas (2), Aromatoleum (1), Bartonella Agrobacterium (1), (1), Polaromonas (1), Dechloromonas (1), Sodalis (1), Rhodoferax Methylobacillus (1), (1), Baumannia Wigglesworthia (23), Eubacterium Butyrivibrio (1), Clostridium (1), Ruminococcus (1), Dorea (5), Coprococcus (1), (1), Faecalibacterium (5), Roseburia (1), Veillonella (1), Megasphaera Oscillospira (1), Selenomonas Propionispira (1), Dialister (1), Peptostreptococcus (1), Mogibacterium (19), (3), Bacteroides (1), Porphyromonas (1), (1), Micrococcus (11), Rikenella Prevotella Escherichia (1), Haemophilus Acinetobacter (1), Neisseria (2), Fusobacterium (3), Sutterella (1) (1), Akkermansia (3), Verrucomicrobium ∼ 400 amount: genera Total ∼ 400–500 species amount: Total Stomach Megasphaera (1), Megasphaera Selenominas (1), Mogibacterium (1), (1), Filifactor Lachnospiraceae (1), Firmicutes sp. (1), phylum Cryptobacterium (1), Atopobium (2), (2), Rothia (4), Actinomyces Corynebacterium (2), Flexistipes (1), Neisseria (3), (1), Delftia Kingella (1), Acidovorax (1), Comarmonas (1), Lautropia (1), Alcaligenes (1), (2), Ralstonia (1), Moraxella (2), Acinetobacter Escherichia (1), Haemophilus (3), Actinobacillus (1), (1), Brevundimonas (1), Caulobacter (1), Blastobacter (1), Pedomicrobium (4), Sphingomonas (3), Campylobacter (1), Helicobacter sp. (3) TM7 phylum genera Total ∼ 100 amount: species Total ≤262 amount: Esophagus Delftia (1), Achromobacter (1), Neisseria (3), Shewanella (1), (1), Yersinia Haemophilus (5), Campylobacter (2), TM7 (3), Bacteroidetes AJ289174 (1), (1), Bacteroides (1), Tannerella Porphyromonas (3), Leptotrichia (2), Fusobacterium (4), Staphylococcus (2), Candida (1), Escherichia (1), (1) Enterobacter genera Total ∼ 594 amount: species Total − amount: ). Oral cavity Oral Rothia (3), Kocuria (1), Arsenicococcus (1), (1), Arsenicococcus (3), Kocuria Rothia (7), (1), Propioibacterium Microbacterium (1), Turicella (3), Dietzia Mycobacterium (1), (5), Gardnerella (1), Corynebacterium (1), Parascardovia (1), Biofidobacterium (1), (2), Slackia (1), Crytobacterium Scardovia (7), Olsenella (4), Eggerthella (1), Atopobium (2), Leptotrichia (9), Sneathia Fusobacterium (4), (56), Bacteroides (19), Prevotella (12), Bergeyella (3), Porphyromonas Tanerella (16), Neisseria (19), (3), Capnocytophaga (1), (5), Acromobacter (2), Kingella Eikenella (1), Burkholderia (1), Lautropia Bordetella (1), (1), Ralstonia (2), Rhodocyclus (3), (1), Leptothrix Variovorax Delftia (1), (1), Xanthomonas Stenotrophomonas (2), Pseudomonas (1), Cardiobacterium (2), (2), Moraxella (6), Acinetobacter (1), Escherichia (3), Klebsiella Enterobacter (1), Haemophilus (1), Proteus (1), Yesinia (1), Aggregatibacter (6), Terrahaemophilus (2), (1), Desulfovibrio (7), Desulfobulbus (1), (1), Bdellpvibiro Desulfomicrobium (4), (1), Sphingomonas Erythromicrobium (1), Afipia (1), Caulobacter Brevundimonas (1), Agrobacterium (3), Bradyrhizobium (1), (1), Ochrobactrum (1), Bartonella (1), Helicobacter (1), Rhizobium Defluvibacter (49), (7) Treponema (1), Campylobacter (1), (1), Jonquetella Chlamydophila (1), Brucella (1), Rickettsia Pyramidobacter (2), Ruminococcus (1), Chlamydia (1), Borrelia (1), (1), Schwartzia (2), Zymophilus (1), Micrococcus (1), Arthrobacter Nocardia (1) Weeksella oralis, (1), Kingella ∼ 365 amount: genera Total ∼ 784 species amount: Total Jandhyala et Jandhyala al. (2015), Gibbons and Houte (1975), Proano et al. (1990), Camilleri et al.(1989), Pei et al. (2004), Bik et al. (2006), et Kroes al. (1999), et Dewhirst al. (2010), et al. Fujio-Vejar (2017), et Dethlefsen al. Table 14. The fundamental physicochemical condition and bacterial diversity in different segments of the digestive tract - (continued) of the digestive segments in different diversity and bacterial condition physicochemical 14. The fundamental Table Data Data from (2006), Berg (1996),Booijink et al (2007), Li et al. (2014), et Wang al. (2005), Stearns et al. (2011), et Zoetendal al. (2012), Li et al. (2015) , Li et al (2018), ) eHOMD and ( http://www.homd.org/ NIH Human Microbiome Project ( https://www.hmpdacc.org/hmp/

42 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Figure 6. Microbial metablism of resveratrol and corresponding enterohepatic/enteroenteric circulation.

(e.g., about 90 and 52% of the total absorbed chrysin and querce- through the bile duct into the upper part of the duodenum and pro- tin, respectively, were transported back to intestinal lumen as ceed to enterohepatic recirculation. For example, about 40% of the mono-/multiple-conjugates and/or non-conjugates). The form of absorbed apigenin was excreted in bile fluid as conjugates (mainly effluent phenolics varies significantly according to the specific 3′-O-methylated glucuronides) (Cai et al., 2007). The left-over in phenolic structures, such as the discrepancy between quercetin the liver will flow into the rest of the body with blood; for querce- (effluent fraction contains 33% quercetin, 43% quercetin glucu- tin, the major forms in systematic circulation are 3′-O-methyl ronidates, and methoxylated quercetin glucuronidates, and 24% glucuronyl sulfate (91.5%), followed by glucuronides and meth- quercetin sulfates) and catechin (effluent fraction is all the origi- oxylated glucuronides of quercetin (8.5%) (Morand et al., 1998). nal catechin) (Donovan et al., 2001). Then the rest of metabolites As for quercetin-4′-glucoside, methylquercetin glucuronyl sulfates (about 14.3% for quercetin) and original phenolics (aglycones or are major metabolites in the blood and quercetin diglucuronides glycosides) arrive at the liver through portal vein before the next are the major metabolites in the gut, liver, and kidney (Graf et al., stags that deliver them in systemic circulation or directly enter into 2005). For catechin, the main plasma metabolites are glucuronide, systemic circulation with lymph (Crespy et al., 1999; Galijatovic methyl, and 3′-O-methyl glucuronides, followed by sulfates (Do- et al., 1999; Walle et al., 1999). novan et al., 2001). No matter in enterocytes or hepatocytes, sulfation, methylation, and glucuronidation proceed fully and it could theoretically produce 7 categories of phenolic metabolites includ- 3.3. Phase II metabolism in hepatocytes ing methylquercetin, quercetin sulfate, methylquercetin sulfate, quercetin glucuronidate, methylquercetin glucuronides, quercetin In the hepatocytes, the original phenolic and enterocytes metabo- glucuronyl sulfates, and methylquercetin glucuronyl sulfates. lites are further metabolized via deglucuronidation as well as glucuronidation, sulfation, methylation, glycination, and phase I metabolism. According to Day et al. (2000a) and O’Leary et al. (2003), 3.4. Phase II enzymatic kinetics the dominant quercetin metabolites from enterocytes, quercetin 7-O-glucuronides, and 3-O-glucuronides, enter into the liver Cai et al. (2007) found that the formation rate of apigenin glucu- where these glucuronides would simultaneously be methylated by ronidation was much faster in both human and mouse liver micro- COMT and deglucuronidated by β-deglucuronidase. The original somes than that of its sulfation. However, the sulfate products were aglycones and aglycone hydrolyzed from quercetin glucuronides the main metabolites recovered in normal mammalian metabolism may be glucuronidated or re-glucuronidated to 3′/4′/5/3/7-O-glu- (Jakoby, 2012). As an example, sulfate conjugation of low-dose curonides (the affinity of UDP-glucuronosyltransferase of querce- chrysin occurred at a rate twice that of glucuronic acid conjugation tin hydroxyl groups followed the order 4′- > 3′- > 7- > 3-, although in both Caco-2 and HepG2 cell lines (Galijatovic et al., 1999). The the maximum rate of formation was for the 7-position, followed by explanation is that the expression of SULTs was much lower than the 3′-position). Presently, there is no study to verify whether the UGTs, at low doses of xenobiotic; sulfate conjugates are predomi- cycle of glucuronidation and deglucuronidation is involved. nant products. However, when phenolics were ingested in high The methylation and sulfation happen at 3′/4′ (mainly 3′-)-po- quantity, the relatively lower amount of SULTs and high substrate sition and 3′/4′/7-position (mainly), respectively (O’Leary et al., dose resulted in a rapid saturation of SULTs. Thus phenolics have 2003). A similar conjugating situation was found in catechin me- to be catalyzed by UGTs, which actually leads to greater produc- tabolism (Donovan et al., 2001). Finally, a large percentage of these tion of glucuronidates (Gradolatto et al., 2004). Similarly, even if phenolic metabolites produced or transited by the liver is secreted COMT shows a similar catalytic rate compared to that of SULTs

Journal of Food Bioactives | www.isnff-jfb.com 43 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. . , . . Labib et al. (2006) Labib et Labib et al. (2006) Labib et Serra et al. (2012) et Serra Labib et al. (2004) Labib et Labib et al. (2004), Labib et al. (2012), et Serra al. (2009) Selma et al. (2006) Labib et Serra et al. (2012) et Serra Yang et al. (2012), et Yang al. (2012) et Serra Citations Zhang et al. (2014), Zhang et al. (2004), Labib et al. (2006), Labib et al. (2004), et Rechner al. (2012) et Serra Pig caecum Pig caecum Rat feces Rat Pig caecum Pig caecum, Pig caecum, feces, rat human feces Pig caecum Rat feces Rat Human feces, Human feces, feces rat Sources Pig caecum, Pig caecum, human feces, feces rat β - — p-hydroxyphenylacetate p-hydroxyphenylacetate decarboxylase — — — — — L-rhamnosidase -D-glucosidase β -D-glucosidase Known enzymes Known — — Clostridium orbiscindens, Clostridium difficile, Clostridium spp. Lactobacillus — — Clostridium scindens, Clostridium desmolans Eubacterium — — Baceroides distasonis, distasonis, Baceroides uniformis, Bacteroides Bacillus ovatuis, Bacteroides sp. 45, sp. 52, Bacteroides sp. 32, 42, 22, Veillonella ramulus Eubacterium Known bacteria Known Eubacterium oxidoreducens, oxidoreducens, Eubacterium orbiscindens, Clostridium ramulus, Eubacterium gilvus, Enterococcus lutetiensis, Stretococcus Lactobacillus Escherichia coli, acidophilus, Weissella Clostridium confusa, Bacteroides perfringens, Butyrivibrio spp. fragilis, p - Phloroglucinol, phenylacetic acid phenylacetic Phloroglucinol, Phloroglucinol, 4-hydroxyphenylacetic 4-hydroxyphenylacetic Phloroglucinol, acid, 4-hydroxytoluene Phenylacetic acid, o - Phenylacetic acid, hydroxyphenylacetic acid p -hydroxybenzoic Eriodictyol, 3-(3-hydroxyphenyl) Eriodictyol, acid, phloroglucinol propionic 3-(2,4-Dihydroxyphenyl)propionic 3-(2,4-Dihydroxyphenyl)propionic acid, 3-(4-hydroxyphenyl) acid, 3-phenylpropionic propionic acid, p - acid, phenylacetic acid, hydroxyphenylacetic acid, o -hydroxyphenylacetic acid, protocatechuic — Phenylacetic acid, Phenylacetic acid, 3,4-dihydroxyphenylacetic acid 3-(2,4-dihydroxyphenyl)propionic Hydrogenated rutin, quercetin- Hydrogenated leucocyanidin, 3-glucoside, flavonone, 5,7,3,4-tetrahydroxy 3-(3,4-dihydroxyphenyl)propionic acid, 3,4-dihydroxyphenylacetic acid, acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, protocatechuic phenylacetic acid, p -hydroxybenzoic acid, phloroglucinol Catabolites 3,4-Dihydroxytoluene, 3,4-Dihydroxytoluene, 3-(3,4-dihydroxyphenyl)propionic acid, 3-(3-hydroxyphenyl)propionic acid, 3,4-dihydroxyphenylacetic acid, p -hydroxyphenylacetic acid, o -hydroxyphenylacetic acid, m -hydroxyphenylacetic acid, acid, protocatechuic acid, phloroglucinol, hydroxybenzoic Galangin Kaempferol Kaempferol rutinoside Kaempferol Flavonones Hesperetin Naringenin Flavone Chrysin Myricetin Rutin and quercetin Rutin and quercetin rhamnoside Phenolic category Flavonols Quercetin Table 15. Overall catabolites of the dietary phenolics by gut microbiota phenolics by of the dietary catabolites 15. Overall Table

44 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds . . . Roowi et al. (2009) et Roowi Labib et al. (2006) Labib et Labib et al. (2006) Labib et Matthies et al. (2011), Matthies al. (2009) Selma et et al. (2011) Matthies Roowi et al. (2009), et Roowi al. (2008) et Tzounis Citations Nielsen et al. (2000) Nielsen et Serra et al. (2012), et Serra al. (2006) Labib et Human gut, human feces, human urine Pig caecum Pig caecum Rat gut Rat gut Rat Human gut, human urine, human feces Sources Rat gut Rat Rat feces, pig feces, Rat caecum — — demethylase — — — Known enzymes Known demethylase — — — — Adlercreutzia equolifaciens, equolifaciens, Adlercreutzia Slackia isoflavoniconvertens, Slackia equolifaciens, garvieae, Lactococcus spp., ovatus Bacteroide intermedius Streptococcus productus, spp., Ruminococcus SNU-Julong 732 (AY310748), EPI1, faecium Enterococcus EPI2, mucosae Lactobacillus magna EPI3, Finegoldia spp. EP and Veillonella Slackia isoflavoniconvertens, Slackia equolifaciens, mucosicola Enterorhabdus Clostridium coccoides coccoides Clostridium and Eubacterium co-cultured rectale Known bacteria Known — — 4-Hydroxyphenylacetic acid, 4-Hydroxyphenylacetic 5-(3′,4′,5′-trihydroxyphenyl)- γ -valerolactone, acid 4-hydroxyphenylacetic 3-Phenylpropionic acid, 3-Phenylpropionic acid, 3-(4-hydroxyphenyl)-propionic acid 3-(4-hydroxyphenyl)-propionic 3-(4-Hydroxyphenyl)propionic 3-(4-Hydroxyphenyl)propionic acid, scutellarein Dihydrodaidzein, equol, Dihydrodaidzein, O-desmethylangolensin 5-hydroxy-equol, Dihydrogenistein, 6′-hydroxy-O-desmethylangolensin 4-Hydroxyphenylacetic acid, 4-Hydroxyphenylacetic acid, 3-(3′-hydroxyphenyl)propionic γ -valeric 5-(3′,4′-dihydroxyphenyl)- acid, 5-(3′,4′-dihydroxyphenyl)- 5-phenyl-γ- γ -valerolactone, acid phenylpropionic valerolactone, Catabolites 4′,6,7-Trihydroxy-5,8- 4′,7-dihydroxy- dimethoxyflavone, 5,6,8-trimethoxyflavone, 4′,6-dihydroxy-5,7,8- 4′-hydroxy- trimethoxyflavone, 5,6,7,8-tetramethoxyflavone, 6-hydroxy-4′,5,7,8- 5,6-dihydroxy- tetramethoxyflavone, 4′,7,8-trimethoxyflavone 3-(3,4-Dihydroxyphenyl)propionic 3-(3,4-Dihydroxyphenyl)propionic acid, 3-(3-hydroxyphenyl)- acid propionic Epigallocatechin Apigenin Hispidulin Isoflavonols Daidzein Genistein Flavanols Catechin/epicatechin Phenolic category Tangeretin Luteolin Table 15. Overall catabolites of the dietary phenolics by gut microbiota - (continued) gut microbiota phenolics by of the dietary catabolites 15. Overall Table

Journal of Food Bioactives | www.isnff-jfb.com 45 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al...... Citations Roowi et al. (2009) et Roowi Grant and Patel (1969), and Patel Grant Heider and Fuchs (1997), Fuchs (2008) . al. (2008) Lupa et Rechner et al. (2004), et Rechner al. (2013) Ludwig et (1969), and Patel Grant al. (2008) et Landete al. (2008) Lupa et Grant and Patel (1969), and Patel Grant al. (1990) et Kluge Barthelmebs et al. et Barthelmebs and (2000), Young (1987) Frazer Knockaert et al. (2012), et Knockaert al. (2007) Bloem et González-Barrio González-Barrio al. (2011b) et Sources Human gut, human feces, human urine Human gut Human gut Human feces fruit, Yogurt, human gut Human gut Human gut, Human gut (Clostridium) gut and chicken (Campylobacter) Yogurt, fruit, Yogurt, human gut Yogurt, fruit, Yogurt, wine gut, human Human feces Known enzymes Known — Decarboxylase, Decarboxylase, transhydroxylase (pyrogallol-phloroglucinol isomerase) decarboxylase Vanillate — 3,4-Dihydroxybenzoate decarboxylase 4-Hydroxybenzoate decarboxylase Decarboxylase Decarboxylase, putative putative Decarboxylase, phenolic acid reductase phenol reductase or vinyl Phenolic acid phenolic decarboxylase, acid acid reductase, phenol reductase — Known bacteria Known — Klebsiella aerogenes, aerogenes, Klebsiella massiliensis, Pelobacter oxidoreducens Eubacterium Bacillus subtilis — aerogenes, Klebsiella plantarum Lactobacillus Bacillus subtilis Klebsiella aerogenes, aerogenes, Klebsiella sp. with a Clostridium sp. co-cultured Campylobacter Lactobacillus plantarum, plantarum, Lactobacillus Enterobacter Bacillus subtilis, DG-6 strain cloacae Lactobacillus collinoides, collinoides, Lactobacillus plantarum, Lactobacillus oeni, Lactobacillus Oenococcus Pediococcus brevis, damnosus, Bacillus coagulans, cerevisiae Saccharomyces Brettanomyces (yeast), anomalus (yeast) — Catabolites Pyrocatechol, pyrogallol, pyrogallol, Pyrocatechol, acid, 4-hydroxyphenylacetic γ - 5-(3′,4′,5′-trihydroxyphenyl)- acid 4-hydroxybenzoic valerolactone, Pyrogallol, phloroglucinol, resorcinol phloroglucinol, Pyrogallol, 2-Methoxyphenol Ferulic acid, caffeic acid, quinic acid, caffeic Ferulic acid, dihydrocaffeic dihydroferulic acid, 3-(3′,4′-dihydroxyphenyl) acid, 3-(3′-hydroxyphenyl) propionic acid, 3-(4′-hydroxyphenyl) propionic acid, 3,4-dihydroxybenzoic propionic acid, acid, phenylacetic acid, 3-hydroxybenzoic benzoic acid, 3′-hydroxyphenylacetic acid, acid, 4-hydroxybenzoic acid, 3-phenylpropionic Catechol Phenol Dihydroxybenzene 4-Vinyl phenol, 3-(4′-hydroxyphenyl) 4-Vinyl acid, 3-phenylpropionic propionic phenol acid, 4-ethyl acid, phenylacetic 4-Vinylguaiacol, dihydroferulic dihydroferulic 4-Vinylguaiacol, acid, 4-ethylguaiacol, alcohol vanillyl vanillin, Ellagic acid, gallic acid, urolithin acid, urolithin Ellagic acid, gallic A A, isourolithin urolithin C, Phenolic category Epigallocatechin- 3-O-gallate Phenolic acids Gallic acid acid Vanillic Chlorogenic acid, Chlorogenic acid feruloyquinic acid Protocatechuic 2/3/4-Hydroxybenzoic acid Dihydroxybenzoic acid Dihydroxybenzoic p -Coumaric acid, acid caffeic Ferulic acid Ferulic Tannins Punicalagin Table 15. Overall catabolites of the dietary phenolics by gut microbiota - (continued) gut microbiota phenolics by of the dietary catabolites 15. Overall Table

46 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds . . . . Williamson and (2010) Clifford Williamson and (2010) Clifford Williamson and (2010) Clifford Flores et al. (2015), et Flores al. (2009) et Ávila Flores et al. (2015), et Flores al. (2009) et Ávila Citations González-Barrio González-Barrio al. (2011b) et Déprez et al. (2000) et Déprez Goel et al. (2011) Goel et Heinonen et al. (2001), Heinonen et al. (2016), et Gaya al. (2003), Xie et al. (2006) et Clavel Aura et al. (2005), et Aura al. (2015), et Flores al. (2017) Chen et Human gut Human gut Human gut Yogurt, human Yogurt, gut, human feces Yogurt, human Yogurt, gut, human gut rat feces, Sources Human feces Human feces Goat feces Goat Human feces Human feces, Human feces, human gut, gut rat — — — β -glycosidase β -glycosidase Known enzymes Known — — tannase deglycosidase, deglycosidase, demethylase, dehydroxylase α ,L-rhamnosidase, β ,D-glycosidase — — — Bifidobacterium lactis Bifidobacterium BB-12, Lactobacillus IFPL722, plantarum, LC-01 casei Lactobacillus Bifidobacterium lactis BB-12, Bifidobacterium plantarum, Lactobacillus casei, Lactobacillus Known bacteria Known — — Enterococcus faecalis Enterococcus Butyribacterium, Butyribacterium, methylotrophicum, callanderi, Eubacterium limosum, Eubacterium Peptostreptococcus Clostridium productus, scindens, Eggerthella lenta — Vanillic acid Vanillic 4-Hydroxybenzoic acid 4-Hydroxybenzoic Syringic acid Syringic Syringic acid, gallic acid, acid, gallic Syringic acid, 2,5-dihydroxyphenylacetic acid, sinapic acid 4-coumaric Gallic acid, 2,5-dihydroxyphenylacetic Gallic acid, 2,5-dihydroxyphenylacetic acid, sinapic acid, 4-coumaric 2,4,6-trihydroxybenzaldehyde, acid, pyrogallol 4-hydroxybenzoic Catabolites Urolithin C, urolithin A, urolithin B A, urolithin urolithin C, Urolithin 2-(4′-Hydroxyphenyl)acetic 2-(4′-Hydroxyphenyl)acetic acid, acid, 3-phenylpropionic acid, 2-(3′-hydroxyphenyl)acetic acid, 3-(4′-hydroxyphenyl)propionic acid, 5-(3′-hydroxyphenyl)valeric acid 3-(3′-hydroxyphenyl)propionic Gallic acid, pyrogallol, resorcinol Gallic acid, pyrogallol, Lariciresinol, secoisolariciresinol, secoisolariciresinol, Lariciresinol, 2,3-bis(3,4- 8-hydroxypinoresinol, dihydroxybenzyl)butene-1,4 enterodiol, diol, sesamol, seco, 2,3-bis(3,4- enterolactone, dihydroxybenzyl)butyrolactone Cyanidin, protocatechuic acid, protocatechuic Cyanidin, acid glucoside, protocatechuic acid, acid, 4-coumaric vanillic 2,4,6-trihydroxybenzaldehyde, hydroxybenzoic acid, caffeic acid tartaric acid, catechol, Peonidin Pelargonidin Malvidin Malvidin-3-glucoside Delphinidin-3- delphinidin glucoside, rutinoside Phenolic category Ellagic acid Proanthocyanidin Tannic acid Tannic Lignans Secoisolariciresinol diglucoside, pinoresinol diglucoside, pinoresinol, medioresinol, syringaresinol, sesamin Anthocyanidins Cyanidin-3-glucoside, cyanidin-3-rutinoside Table 15. Overall catabolites of the dietary phenolics by gut microbiota - (continued) gut microbiota phenolics by of the dietary catabolites 15. Overall Table

Journal of Food Bioactives | www.isnff-jfb.com 47 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. . Landete et al. et Landete and (2008), Marsilio (1998) . Lanza Scheline (1968b) Scheline (1968a) Citations Williamson and (2010), Clifford al. (2016) Cheng et Braune et al. (2005) et Braune Tan et al. (2015), et Tan al. Hassaninasab et al. (2017), (2011), An et al. (2002) et Ireson Olive brines, Olive be found could in human gut Rat feces, feces, Rat caecal, rat feces rabbit Rat gut Rat Sources Yogurt, human Yogurt, gut, human feces Human gut Human feces, Human feces, mice feces -glucosidase, esterase β -glucosidase, — — Known enzymes Known — -glucosidase, β -glucosidase, hydrolase phloretin NADPH-dependent NADPH-dependent curcumin/ dihydrocurcumin reductase Lactobacillus plantarum Lactobacillus — — Known bacteria Known Lactobacillus plantarum plantarum Lactobacillus GIM 1.35, Streptococcus thermophiles GIM 1.321, Eubacterium ramulus, ramulus, Eubacterium orbiscindens Clostridium Escherichia coli., Bacillus Escherichia coli., DCMB-002, megaterium longum Bifidobacterium BB536, Bifidobacterium G4, pseudocatenulatum acidophilus, Lactobacillus shirota, casei Lactobacillus JCM faecalis Enterococcus K-12 5803, Escherichia coli Hydroxytyrosol Dihydrocoumarin, Dihydrocoumarin, acid, 2-hydroxyphenylpropionic acid 2-hydroxyphenylacetic Protocatechuic acid, catechol Protocatechuic Catabolites Protocatechuic acid, caffeic acid, acid, caffeic Protocatechuic 3-(3′,4′-hydroxyphenyl)propionic acid, 3-(3′-hydroxyphenyl)propionic acid, 3-(4′-hydroxyphenyl)propionic acid, 3′,4′-dihydroxyphenylacetic acid, 4′-hydroxyphenylacetic acid, acid, 3,4-dihydroxybenzoic resorcinol, catechol, pyrogallol, Hesperetin dihydrochalcone dihydrochalcone Hesperetin hesperetin 4′- β -d-glucoside, 3-(3-hydroxy- dihydrochalcone, 4-methoxyphenyl)propionic acid, 3-(3,4-dihydroxyphenyl) acid, phloroglucinol propionic Tetrahydrocurcumin, Tetrahydrocurcumin, demethoxycurcumin, bisdemethoxycurcumin, acid, 1-(4-hydroxy- dihydroferulic 3-methoxyphenyl)-2-propanol, demethyl bis-hydroxylated methylated dihydrocurcumin, hydroxylated tetrahydrocurcumin, dihydrocurcumin, and demethylated 3,5-tetrahydropyrandione demethyl dehydroxyl derivative, 3,5-tetrahydropyrandione hexahydrocurcumin derivative, Oleuropein Coumarin Quinic acid Phenolic category Cyanidin Chalcone Neohesperidin dihydrochalcone Others Curcumin Table 15. Overall catabolites of the dietary phenolics by gut microbiota - (continued) gut microbiota phenolics by of the dietary catabolites 15. Overall Table

48 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds overall (Tables 11, 12), the lower expression of COMT might limit drolyzed into free micro-molecules (from bound phenolics to free the yield of methyl conjugates. Furthermore, the substitution sites phenolics, from complex phenolics to simple phenolic acids), or of sulfation (3′/4′/7) and methylation (3′/4′) are more similar than originate from fundamental nutrients but further be metabolized those of glucuronidation (7/5/3/3′/4′). Thus all these factors might and converted into bioactive compounds (from carbohydrates/pro- demonstrate the phenomenon that the percentage of phenolic glu- tein/fatty acids to short-chain fatty acids and vitamins B/K) (Ram- curonidates is always the highest among phase II metabolites when akrishna, 2013). Generally, dietary phenolics flowing into colon high-dose phenolics is administrated. In in vivo metabolism, doz- mainly exist in the bound or conjugated forms. Therefore, the most ens of these known enzymes may catalyze phenolics in a competi- common step of phenolic degradation process is deconjugation tive and random way rather than in the fixed steps even if they have such as demethylation of ferulic acid, deglucuronidation of querce- discrepancies in both total amount and reaction rate. This results in tin 3-O-glucuronic acid and deglycosylation of quercetin 3-O-glu- metabolites produced in diversified conjugated position and to dif- coside. By the way, the oral cavity also contains a trace amount of ferent extent, and thus much more metabolites are generated than deglycosylation products of flavonoids due to the action of the oral proposed above (Fig. 3) (Crespy et al., 1999; Graf et al., 2005; microbes (Walle, 2004). The disassociation of C–C/C–O bonds be- Morand et al., 1998). The specific species of metabolites and the tween phenolic oligomers/polysaccharides and phenolic terminal extent of metabolism are distinct, depending on enzymatic distri- thereof contributes to the exposure of free phenolics and sugars in bution and expression level in different tissues, along with respec- the colon and provide the carbon source for bacterial consumption tive phenolic-enzyme affinity (Table 13, Fig. 3–5). More selectiv- (Mosele et al., 2015; Shahidi and Yeo, 2016). Along with decon- ity and reaction orders of different flavonoids in glucuronidation jugation, the similar conjugation types of phase II metabolism, have appeared elsewhere (Wong et al., 2009). sulfation and methylation were also proposed to occur in the op- When phenolics are orally administrated as drugs, before arriv- posite direction as the first step of phenolic catabolism because the ing into targeted sites, the activity and amount decline caused by sulfated and methylated catabolites are detected in the in vitro test, metabolic modification and subsequent efflux in the intestine and even though the earlier study denied the possibility of methylation liver, known as the first-pass metabolism. During enterohepatic by gut bacteria (Aura et al., 2002; Kim et al., 1992; Yang et al., and enteroenteric recirculation, some of the reabsorbed phenolics 2012). Of course, in the in vivo test instead, these conjugates are will enter into the whole circular system, but most of them would most likely re-synthesized through the colonic reabsorption and in still be passed to the large intestine with unabsorbed and bound vivo metabolism and subsequently secreted into intestinal lumen phenolics. Consequently, the poor digestibility, absorbability, ef- during enteroenteric and enterohepatic circulation (Fig. 6). ficient biotransformation, and efflux mechanism yield a consider- In the same manner as phenolic absorption in the small intes- able amount of phenolics to be fermented by the colon microor- tine, the newly released free phenolics and unabsorbed free pheno- ganism. lics of upper tracts could be absorbed by colonic enterocytes and metabolized through the phase I and II routines, as was explained in the previous section on metabolism. In parallel, upon anaero- 4. Colonic fermentation bic fermentation of released monomers such as glucose, amino acids, and fatty acids, phenolic aglycones in the colon may further be bio-converted through multiple-enzyme effects and finally After digestion and absorption in the small intestine, the rest of transformed to simpler phenolics. These decomposed products the chyme consists of undecomposable residues, unabsorbed generally present as (but not limited to) hydroxyphenylpropionic soluble ingredients, and enterohepatic/enteroenteric circulation acid, hydroxyphenylacetic acid, dihydroxybenzene, benzoic acid, fractions that are passed to the lower intestinal tract and finally hydroxybenzoic acid, trihydroxybenzaldehyde, catechol and their proceed to colonic anaerobic fermentation. Compared with the derivatives (Table 15). The in vivo metabolism and gut catabolism proximal digestive tracts, the colon possesses the highest micro- 12 usually process sequentially on the same catabolite, such as hy- organisms population at a density of 10 organisms per gram of droxyhippuric acid, 3-(4′-hydroxyphenyl)lactic acid, glucuronyl- luminal content, which is involved in maintaining of host’s intes- dihydroresveratrol sulfate and 3′-methoxy-4′-hydroxyphenylacetic tinal homeostasis and a relatively longer stay duration (50–90% acid are the products subjected to glycination, hydroxylation, of the total digestion duration), thus acting as the major site for glucuronidation/sulfation and methylation from hydroxybenzoic food residue fermentation by gut microorganism (Table 14). These acid, 3-(4′-hydroxyphenyl)propionic acid, dihydroresveratrol, and colonic microorganisms are mainly the anaerobic bacteria which 3′,4′-dihydroxyphenylacetic acid, respectively (González-Barrio et consist of more than 500 species and about 100 phyla including al., 2011b; Rotches-Ribalta et al., 2012a). Thus, the final absorbed Firmicutes (65.7% of 19,548 classified sequences), Bacteroidetes phenolics are not only the orally administrated phenolics and their (16.3%), Proteobacteria (8.8%), Actinobacteria (4.7%) and Ver- in vivo metabolites, but also their gut catabolites and the in vivo rucomicrobia (2.2%) (Garrett et al., 2010; Hidalgo et al., 2012; metabolites of absorbed catabolites. To a great extent, postprandial Ley et al., 2008). However, when using all the specific body of long-term bioaccessibility of phenolics is affected by these con- data for one group or one species it at best is providing an excellent verted metabolites in the colon. The classical pharmacokinetics, generalization rather than a strict answer. No matter in any seg- therefore, cannot thoroughly quantify the phenolic bioavailabil- ments of the digestive tract, inter-individual and intra-individual ity, namely the in vivo bioavailability of phenolics defined by the variations in microbial quantity and diversity are significant due to concentration of native phenolics and their conjugated metabolites different age, race, gender, health condition, medication usage, di- without considering absorbed colonic catabolites is less than the etary habit, and environmental microbiome, most of which have to actual value. To be more specific, bioaccessibility of resveratrol be individually described and still need to be further investigated ranged from 36.3 to 84.9% within 24 hours, herein, 8.1–62.7% (Costello et al., 2009; Cotillard et al., 2013; Xu and Knight, 2015). of absorbed resveratrol were in the form of microbial metabolites Literally, gut bacteria and their host mutually benefit from one an- including dihydroresveratrol, 3,4′-dihydroxy-trans-stilbene and other; bacteria achieve culture medium and produce/liberate the lunularin (Bode et al., 2013). The postprandial short-term bioac- bioactive substances to the host at the same time. These bioaccessibility of ellagitannins is zero until being slightly metabolized tive products may bind to food matrices and are subsequently hy- into urolithin C/D starting by the jejunum bacteria, followed by

Journal of Food Bioactives | www.isnff-jfb.com 49 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Figure 7. Microbial metabolism of ellagitannin. massive dehydroxylation into urolithin A/B/C/D in the colon (Fig. into simpler phenolic acids but exerts no catabolic capacity when 7) (Gaya et al., 2016). there is no sugar moiety on aglycone, while Eubacterium oxidore- Meanwhile, the bioactivity of the new metabolites is signifi- ducens works on both quercetin glycosides and aglycones (Table cantly distinct from their precursors. Gakh et al. (2010) found that 16) (Winter et al., 1989). From another point of view, these bacte- dihydroresveratrol, the microbial product of resveratrol, could pro- ria with their unique characters could collaboratively decompose mote proliferation of MCF-7 cell line at picomolar-range concen- dietary phenolics. For example, the Bacteroides spp., one of the tration but not by its parental compound. Forester and Waterhouse most common and large-quantity gut flora, hydrolyze flavonoids (2010) demonstrated that gallic acid, 3-O-methylgallic acid, and glycosides, followed by aglycones’ decomposition by Clostridium 2,4,6-trihydroxybenzaldehyde are more effective in reducing the orbiscindens, Butyrivibrio sp. C3, and Eubacterium oxidoredu- proliferation of Caco-2 than their precursor anthocyanins. Setchel cens. Other gut bacteria involved in phenolic catabolism are given et al. (2002) also reported that equol showed a greater antioxidant in Table 15 and also appear in several reviews (Aura, 2008; Braune activity and higher affinity (10–80 times) to the estrogen receptorα and Blaut, 2016; Selma et al., 2009). Obviously, distinct principal and β than the corresponding native isoflavones. As well,Monagas skeletons of aglycones would be disposed by different enzymes et al. (2009) showed that the most common catabolites from fla- and result in various metabolism pattern. Besides, as already men- vonoids, 3,4-dihydroxyphenylpropionic acid, and 3,4-dihydroxy- tioned, the inter-individual variation results in a huge variety in phenylacetic acid, could inhibit 85–98% production of cytokines species of individual gut flora and also contributes to a potential (TNF-α, IL-1β, and IL-6) in lipopolysaccharide (LPS)-stimulated difference of the catabolism pattern on the same phenolics. Gross peripheral blood mononuclear cells. On the other hand, the bacte- et al. (2010) reported the differences of tea catabolism by the gut rial transformation may result in the loss of native bioactivities, flora of 10 feces donors, the catabolites gallic acid and pyrogallol such as desmethylangolensin, another product of daidzein, has no of tea polyphenols ranged from 0.05 to 0.82 mM at 8th hour and human estrogen-like effect (De Boever et al., 2000). More health 0 to 0.25 mM at 70th hour, respectively. After 72 hours in vitro fe- effects including inhibition of tumor, mutation, inflammation, oxi- cal incubation of the red wine/grape juice phenolics, the catabolic dative stress, hormone level, blood sugar level and various gut dis- intermediates (3-hydroxyphenylacetic acid and phloroglucinol) eases exerted by phenolic gut catabolites in chemical and cellular were absent in several donors’ feces sample but were abundantly level has already been reviewed (Aura, 2008; Chiou et al., 2014; present within other incubations. In the study of in vitro human Monagas et al., 2010; Tuohy et al., 2012). fecal incubation of ellagic acid, the catabolites consisting of uro- In anaerobic degradation of phenolic aglycones, there are two lithin A, isourolithin A, and urolithin C were formed in most of main purposes for gut microbe to modify the side chains and het- the incubations, exceptionally, one of them could also produce erocyclic ring of phenolics; the first is to achieve the carbon source urolithin B (González-Barrio et al., 2011a). Apart from the inter- and energy to survive, the second is to decrease the original tox- individual variation, intra-individual condition altering including icity of phenolics themselves (Mosele et al., 2015). Oleuropein aging, stress, disease and dietary habit also ignites the qualitative and protocatechuic acid, for instance, could inhibit the growth of and quantitative change of gut flora and corresponding phenolic Lactobacillus plantarum, but their catabolites including hydroxy- catabolism. Thus, inter-/intra-individual variation in gut phenolic tyrosol, elenoic acid, and catechol transformed by Lactobacil- biotransformation significantly affects phenolic bioavailability and lus plantarum have no inhibitory effect anymore (Landete et al., potential bioactivity. 2008). On the other hand, two colonic obligate anaerobic bacteria Overall, the principal reactions of phenolic aglycones may in- Bacteroides iuniformis and Bacteroides ovatuis can only utilize clude hydrolysis, reduction, and oxidation. In terms of phenolic the sugar moiety of flavonoid glycosides and produce aglycones biotransformation, these reactions could be divided into periph- without any further catabolism (Winter et al., 1989). More inter- eral and central aromatic metabolism. The peripheral metabolism estingly, Butyvriiibrio spp. could catabolize quercetin glycosides contains heterocyclic-ring cleavage, de-esterification, de-etherifi-

50 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds . Citation al. (2002), et Aura al. (2004), et Rechner al. (1999) Schneider et al. (1969) Cheng et al. (1969) Cheng et al. (2002) et Aura al. (1971) Cheng et al. (1999) Schneider et al. (1989) et Winter al. (2005) et Braune al. (2005) et Braune al. (1991), et Winter al. (1999) Schneider et Source Human feces Human gut, rumen bovine Human gut, rumen bovine Human feces Human gut, rumen bovine Human feces, rumen bovine Human gut Human gut Human gut Human feces Species distasonis, Bacteroides uniformis, Bacteroides ovatus, Bacteroides casseliflavus, Enterococcus JY-6, Bacteroides faecium, Enterococcus Selenomonas ruminatium, Butyrivibrio fibrisolvens D1, Peptostreptococcus sp. sp. B178, Coprococcus milleri P15, Streptococcus Butyrivibrio sp. C3 Butyrivibrio sp. C3 Butyrivibrio sp. C3 ramulus, Eubacterium Butyrivibrio sp. C3, oxidoreducens Eubacterium distasonis Bacteroides ramulus Eubacterium ramulus, Eubacterium orbiscindens Clostridium orbiscindens, Clostridium Butyrivibrio sp. C3, oxidoreducens Eubacterium β -rhamnosidase Enzymes β -Glucosidase, Glycosidases — β -Glucuronidases — Desmolase ( β -glycosidase) β -Glucosidase hydrolase phloretin — Products Quercetin Quercetin 4-Hydroxyphenylacetic acid (ring B), 3, 4-dihydroxyphenylacetic acid (ring B), 3,4-dihydroxybenzaldehyde (ring B), phloroglucinol (ring A), CO2 Quercetin acid 4-Hydroxyphenylacetic (ring A) (ring B), phloroglucinol Quercetin, 3,4-dihydroxybenzaldehyde (ring B), acid 3,4-dihydroxyphenylacetic (ring (ring B), phloroglucinol lactate acetate, A), butyrate, Kaempferol dihydrochalcone Hesperetin 3-(3-Hydroxy-4- acid methoxyphenyl)propionic 4-Hydroxyphenylacetic acid (ring B), 3, acid 4-dihydroxyphenylacetic (ring A) (ring B), phloroglucinol Precursors Quercetin glucoside glucoside Quercetin and rutin Rutin, quercitrin Quercetin glucuronidates Quercetin Naringenin glucoside Quercetin Robinin Hesperetin dihydrochalcone 4′- β -d-glucoside Hesperetin dihydrochalcone quercetin Kaempferol, Table 16. The single catabolic step with specific enzymes and bacteria with specific enzymes step 16. The single catabolic Table

Journal of Food Bioactives | www.isnff-jfb.com 51 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. Citation al. (2009) et Ávila Ávila et al. (2009) et Ávila (2000) Hur and Rafii (2000) Hur and Rafii (2000) Hur and Rafii al. (2006) Labib et al. (2006) Labib et al. (2006) Labib et al. (2006) Labib et (1987) and Frazer Young al. (2006) Labib et al. (2017), et Ricaboni al. (1999) Schneider et (1995) He and Wiegel al. (1999) Schneider et al. (1989) et Winter Source Human feces Human gut Human gut Human gut feces Swine Human gut Pig caecum Human feces — Human feces Human, gut piglet Rumen animals Human gut Human gut Species lactis Bifidobacterium BB-12, Lactobacillus IFPL722, plantarum LC-01 casei Lactobacillus lactis Bifidobacterium BB-12, Lactobacillus IFPL722, plantarum LC-01 casei Lactobacillus Eubacterium limosum Eubacterium limosum Eubacterium limosum Eubacterium ATCC difficile Clostridium spp. 9689, Lactobacillus difficile Clostridium limosum Eubacterium — — and Escherichia coli var. faecalis Streptococcus co-cultured liquifaciens Acidaminococcus fermentuns, ramulus Eubacterium pneumoniae Klebsiella ramulus Eubacterium oxidoreducens Eubacterium Enzymes — — Demethylase Demethylase Demethylase p -Hydroxyphenylacetate decarboxylase p -Hydroxyphenylacetate decarboxylase Demethylase Dehydroxylase Decarboxylase Dehydroxylase Hydroxybenzoyl-CoA benzoyl-CoA reductase, 2-hydroxyglutaryl- reductase, CoA dehydratase 4-Hydroxybenzoate decarboxylase reductase Phloroglucinol — -coumaric acid p -coumaric acid p -coumaric Products Syringic acid, gallic acid (ring acid, gallic Syringic B), 2,5-dihydroxyphenylacetic acid (ring B), (ring B), sinapic acid B) acid (ring B), Syringic acid (ring B), gallic 2,5-dihydroxyphenylacetic acid (ring B), (ring B), sinapic acid B) Daidzein Genistein 6,7,4′-Trihydroxyisoflavone 4-Hydroxytoluene 3,4-Dihydroxytoluene Scutellarein, 6,7,4′-trihydroxyisoflavone, daidzein genistein, acid 3-Phenylpropionic 4-Ethylphenol 3-(3-Hydroxyphenyl) acid propionic acid, acetyl Benzoic CO2 group, Phenol 1,3-Dioxo-5-hydroxy- cyclohexane 1,3-Dioxo-5-hydroxybutyrate acetate, cyclohexane, Precursors Malvidin glucoside Delphinidin glucoside Formononetin Biochanin A Glycitein 4-Hydroxyphenylacetic acid 3, 4-Dihydroxyphenylacetic acid Hispidulin, glycitein, biochanin A, formononetin 3-(4′-Hydroxyphenyl) acid propionic 3-(4′-Hydroxyphenyl) acid propionic 3-(3′,4′-Dihydroxyphenyl) acid propionic acid Hydroxybenzoic acid Hydroxybenzoic Phloroglucinol Phloroglucinol Table 16. The single catabolic step with specific enzymes and bacteria - (continued) and bacteria with specific enzymes step 16. The single catabolic Table

52 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds Citation al. (1990) et Kluge al. (2006) et Clavel al. (2006) et Clavel al. (2006) et Clavel al. (2006) et Clavel al. (2006) et Clavel al. (2005) et Possemiers (1969) and Patel Grant al. (2008) Lupa et al. (2008) Lupa et (1987) and Frazer Young (1969) and Patel Grant Source Human gut (Clostridium) gut and chicken (Campylobacter) Human gut Human gut Human gut Human gut Human gut Human feces Human feces Human gut Human gut Sludge (Clostridium KN245), strain gut Bird (Campylobacter sp.) Human gut Species sp. with Clostridium a Campylobacter sp. Co-cultured sp., Bacteroides Clostridium fragilis, Bacteroides ovatus, distasonis, Bacteroides C. cocleatum, B. fragilis, ramosum Clostridium Butyribacterium methylotrophicum, callanderi, Eubacterium limosum, Eubacterium Peptostreptococcus Bacteroides productus, methylotrophicum scindens, Clostridium Eggerthella lenta, Peptostreptococcus productus amygdalinum, Clostridium saccharolyticum, Clostridium ED-Mt61/PYG-s6 Strain ED-Mt61/PYG-s6 Strain limosum Eubacterium aerogenes Klebsiella Bacillus subtilis Bacillus subtilis KN245 strain Clostridium and Campylobacter sp. Co-cultured aerogenes Klebsiella Enzymes reductase Resorcinol Deglycosidase Demethylase Dehydroxylase Dehydrogenase Dehydrogenase Demethylase 3,4-Dihydroxybenzoate decarboxylase decarboxylase Vanillate 4-Hydroxybenzoate decarboxylase Decarboxylase Decarboxylase Products 1,3-Cyclohexanedione Secoisolariciresinol 2,3-Bis(3,4-dihydroxybenzyl) diol butene-1,4 Enterodiol Enterolactone 2,3-Bis(3,4-dihydroxybenzyl) butyrolactone 8-Prenylnaringenin Catechol 2-Methoxyphenol Phenol resorcinol Pyrogallol Precursors Resorcinol Secoisolariciresinol diglucoside Secoisolariciresinol 2,3-Bis(3,4- dihydroxybenzyl) diol butene-1,4 Enterodiol 2,3-Bis(3,4- dihydroxybenzyl) diol butene-1,4 Isoxanthohumol acid Protocatechuic acid Vanillic acid 4-Hydroxybenzoic 2,4/6-Dihydroxybenzoic acid Gallic acid Table 16. The single catabolic step with specific enzymes and bacteria - (continued) and bacteria with specific enzymes step 16. The single catabolic Table

Journal of Food Bioactives | www.isnff-jfb.com 53 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. . Citation Heider and Fuchs (1997), Fuchs (2008) Scheline (1968a) al. (1987) et Krumholz al. (1987) et Krumholz al. (1987) et Krumholz al. (1987) et Krumholz al. (1990) et Kluge (1969), and Patel Grant al. (1990) et Kluge al. (2000) et Barthelmebs al. (2012), et Knockaert al. (2007) Bloem et al. (2012) et Knockaert Source Human gut Rabbit feces, feces rat Could be from extracted human gut Could be from extracted human gut Could be from extracted human gut Could be from extracted human gut Human gut (Clostridium) gut and chicken (Campylobacter) Human gut, Human gut (Clostridium) gut and chicken (Campylobacter) be found could in human gut fruit, Yogurt, human gut fruit, Yogurt, human gut Species massiliensis, Pelobacter oxidoreducens Eubacterium — oxidoreducens Eubacterium oxidoreducens Eubacterium oxidoreducens Eubacterium oxidoreducens Eubacterium sp. with Clostridium a Campylobacter sp. Co-cultured aerogenes, Klebsiella sp. with Clostridium a Campylobacter sp. Co-cultured plantarum, Lactobacillus Bacillus subtilis collinoides, Lactobacillus plantarum, Lactobacillus oeni, Oenococcus brevis, Lactobacillus damnosus, Pediococcus spp. Pediococcus plantarum Lactobacillus Enzymes (pyrogallol- Transhydroxylase isomerase) phloroglucinol Dehydroxylase reductase Phloroglucinol Dihydrophloroglucinol hydrolase CoASH p -Hydroxybutyryl-CoA CoA dehydrogenase, butyryl-CoA transferase, acetyl-CoA dehydrogenase, enoyl- acetyltransferase, phosphate CoA hydrase, acetate acetyltransferase, kinase kinase, butyrate Dehydroxylase Decarboxylase Decarboxylase Phenolic acid decarboxylase Phenolic acid reductase Products Phloroglucinol Resorcinol dihydrophloroglucinol 3-hydroxy-5-oxohexanoate 3-hydroxybutyryl- CoA, acetyl-CoA and butyrate acetate Phenol Dihydroxybenzene phenol 4-Vinyl 4-Vinylguaiacol acid Dihydroferulic Precursors Pyrogallol Pyrogallol Phloroglucinol Dihydrophloroglucinol 3-hydroxy-5- oxohexanoate. 3-hydroxybutyryl-CoA 2/3/4-Hydroxybenzoic acid acid Dihydroxybenzoic p -Coumaric acid acid Ferulic acid Ferulic Table 16. The single catabolic step with specific enzymes and bacteria - (continued) and bacteria with specific enzymes step 16. The single catabolic Table

54 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds Citation Young and Frazer (1987) and Frazer Young al. (2012) et Knockaert al. (2007) Bloem et al. (2007) Bloem et Scheline (1968a) (1998) and Lanza Marsilio (1998) and Lanza Marsilio Hassaninasab et al. (2011) Hassaninasab et al. (2011) Scheline (1968b) Source Yogurt, fruit, Yogurt, human gut fruit, Yogurt, human gut Wine caecal Rat brines Olive brines Olive Human feces Human feces caecal, Rat Species faecium, Streptococcus sp., Lactobacillus aerogenes, Enterobacter Bacillus sp. Lactobacillus plantarum Lactobacillus plantarum, Lactobacillus oeni, Oenococcus brevis, Lactobacillus damnosus Pediococcus oeni, Oenococcus Bacillus coagulans, cerevisiae Saccharomyces Brettanomyces (yeast), anomalus (yeast) — B21 plantarum Lactobacillus B21 plantarum Lactobacillus DH10B Escherichia coli. DH10B Escherichia coli. — Enzymes Decarboxylase Acid phenol reductase — — Esterase β -Glucosidase Esterase curcumin/ NADPH-dependent reductase dihydrocurcumin curcumin/ NADPH-dependent reductase dihydrocurcumin Esterase Products 4-Vinylcatechol 4-Ethylguaiacol Vanillin alcohol Vanillyl Gallic acid Oleuropein-aglycone elenolic acid Hydroxytyrosol, Dihydrocurcumin Tetrahydrocurcumin 2-Hydroxyphenylpropanoic acid Precursors Caffeic acid Caffeic 4-Vinylguaiacol acid Ferulic Vanillin gallate Methyl Oleuropein Oleuropein-aglycone Curcumin Dihydrocurcumin Dihydrocoumarin Table 16. The single catabolic step with specific enzymes and bacteria - (continued) and bacteria with specific enzymes step 16. The single catabolic Table

Journal of Food Bioactives | www.isnff-jfb.com 55 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Figure 8. Microbial metablism of cinnamic acid esters.

Figure 9. Microbial metablism of proanthocyanin.

56 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Figure 10. Microbial metablism of isoflavones. cation, carboxylation, decarboxylation, demethylation, dihydrox- yhydroxycinnamic acid patterns; Fig. 6, 8, 9) (Bode et al., 2013; ylation, and addition reaction. Herein, the most important stage Ludwig et al., 2013; Rechner et al., 2004; Rotches-Ribalta et al., is oxidation, including α/β-oxidation that usually breaks the C–C 2012b). Hydrolysis occurs at the ester linkage of phenolics such covalent bonds of the side chain of phenolic acids and the A/C ring as chlorogenic acid, catechin gallate, and oleuropein which could of flavonoids, leading to the shortening of the side chains with the break the molecules to simpler phenolics and organic acids (Mo- formation of a carboxyl group (poly-hydroxy cinnamic acid pat- sele et al., 2015). The central aromatic metabolism (oxidative and tern, Fig. 8), as well as the A/C-ring fission (e.g. catechin, isofla- reductive fission of phenyl ring) by human gastrointestinal flora vonoids, flavonoids, and anthocyanidins, Fig. 9–12) with produc- is rare and with only few investigations (Heider and Fuchs, 1997; tion of phenolic acids. Phenolic reduction by gut bacteria includes Selma et al., 2009). Currently, even though human gut still lacks a reductive cleavage of C-ring ether and ketone bonds (e.g., lignans rigorously clarified reaction chain of aromatic degradation similar and flavonoids) and hydrogenation of carbon double bonds on ei- to those proven in natural soil, water or mine sites and environ- ther the alkyl side chain (e.g., coumaric acid) or the heterocyclic ment, several simple phenolic products of bacterial fermentation ring (e.g., isoflavonoids, flavonoids, and lignans, Fig. 10, 11, 13). such as benzoic acid, pyrogallol, phloroglucinol, and resorcinol Moreover, dehydroxylation and decarboxylation are also reduction are still thought to rapidly go through central aromatic metabo- reactions of which their extent of sensitively depends on specific lism including aerobic pathway (e.g. gentisic acid, ortho-cleavage, phenolic structures (resveratrol, polyhydroxybenzoic acid and pol- and meta-cleavage pathway) and anaerobic pathway (e.g. benzo-

Figure 11. Microbial metablism of flavone, flavonol, flavanone and flavanonol.

Journal of Food Bioactives | www.isnff-jfb.com 57 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al.

Figure 12. Microbial metablism of anthocyanidin. yl-CoA pathway), and be degraded into CO2, succinyl-CoA, and rium oxidoreducens isolated from the human gut are also able to acetyl-CoA (e.g. 3 acetyl-CoA and 1 CO2 or 2 acetyl-CoA and 0.5 reduce phloroglucinol into 1,3-dioxo-5-hydroxy-cyclohexane and butyryl-CoA) in the gut (Fuchs, 2008; Heider and Fuchs, 1997; further decompose into acetate and butyrate (Table 16) (Ricaboni Toromanović et al., 2008). As exemplified, the flavonoid A ring et al., 2017; Schneider et al., 1999; Winter et al., 1989). Interest- metabolite (phloroglucinol) and the fission product of heterocyclic ingly, besides the multifarious catabolic reactions described above, ring of flavonoids, could hardly be detected, indicating its rapid an aromatization was observed in the in vitro incubation of quinic consumption by gut microorganism (Labib et al., 2006). The best and shikimic acids by rat caceal extract, these two simple multi- known aromatic central degradation has so far been produced by hydroxyl cyclohexane carboxylic acids could be converted to pro- Acidaminococcus fermentuns found in pig and human gut which tocatechuic acid, then be further catabolized to catechol (Scheline, may enable hydroxybenzoic acid catabolizing to benzoic acid, 1968a). acetyl group, and CO2. The Eubacterium ramulus and Eubacte- It is important to emphasize that even though taxonomic and

Figure 13. Microbial metablism of lignan.

58 Journal of Food Bioactives | www.isnff-jfb.com Shahidi et al. Bioaccessibility and bioavailability of phenolic compounds

Table 17. Catabolism rate of phenolic extracts of nuts-cocoa cream by rat colonic microflora

Substrate concentration in Percentage (%) remained after incubation, h Substrate diluted rat fecal inoculum, pM 1 2 4 24 48 Rutin 23.0 95.7 ± 9.1 87.0 ± 7.4 75.5 ± 6.1 1.5 ± 0.1 1.4 ± 0.1 Quercetin rhamnoside 7.3 111.0 ± 10.7 108.2 ± 10.4 27.4 ± 2.6 7.7 ± 0.4 0.8 ± 0 Quercetin 1.0 64.0 ± 3.0 110.0 ± 11.0 370.0 ± 31.0 33.0 ± 2.0 0 Kaempferol-rutinoside 9.0 97.8 ± 9.7 98.9 ± 7.2 87.8 ± 3.6 0.2 ± 0 0 Naringenin 13.0 100 ± 0.9 76.9 ± 7.6 36.2 ± 2.5 50.8 ± 4.9 0 Luteolin 32.0 93.8 ± 9.4 90.6 ± 6.6 46.9 ± 4.4 29.7 ± 2.9 15.6 ± 1.5 Gallic acid 43.0 148.8 ± 14.2 155.8 ± 14.0 134.9 ± 1.3 74.4 ± 7.2 65.1 ± 5.3 Protocatechuic acid 296.0 95.9 ± 8.1 97.3 ± 5.7 89.5 ± 7.1 92.2 ± 8.4 85.8 ± 7.1

Adapted from Serra et al. (2012). quantitative differences exist in individuals, people may possess also been widely reported (Ferreira et al., 2017; Shahidi and Am- the same phenolic catabolism capacity in the gut as the bacteria bigaipalan, 2015). These natural phenolics are also used as sup- from distinct genera are able to catalyze the same reaction. The plements or drugs. Several well-developed phenolic supplements genes encoding a core activity from different taxa are called “func- could easily be found in the wholesale and pharmacy outlets in- tional core” and diverse gut microorganism managing the identical cluding Lipo-Flavonoid® (lemon phenolic extract with Eriodictyol reaction from different individuals may be called “core microbi- Glycoside), and Daflon (90% diosmin and 10% hesperidin). Other ome” (Turnbaugh et al., 2009; Willson and Situ, 2018). Compared prescription drugs such as Veregen® ointment (catechin deriva- with the only two well-known enzymes LPH and cinnamoyl ester- tives) and Mytesi™ tablets (oligomeric proanthocyanidin mixture) ase that catalyze de-esterification in the small intestinal lumen, the have been confirmed as commercial drugs by US FDA. Beyond enzymes for colonic microbial decomposition are more compli- natural phenolic products, traditional synthetic phenolics such as cated and diverse as shown in Table 14. Consistent with all other BHT (butylated hydroxytoluene), BHA (butylated hydroxyani- enzymatic reaction, distinct substrates with identical core structure sole), TBHQ (tertiary-butylhydroquinone), TBMP (2-tert-butyl- catalyzed by the same gut flora render a significantly different re- 4-methylphenol), PG (propyl gallate), and aspirin (acetylsalicylic action rate (Tables 17 and 18). Hence, understanding the phenolic acid) are permitted and employed in food processing and phar- catabolism variability in gut microbiota across various substrates maceutical industries. Meanwhile for the sake of increasing their and consumer groups, and correlating it with specific functions of bioavailability as well as enhancing safety and application range, gut catabolites, is going to serve as a reference for consumption of numerous novel phenolics such as phenolic fatty acid esters and phenolics with healthful effects. phenolic amino acid esters have been synthesized and further tests on their physiochemical and bioactive properties have been reported (Oh et al., 2018; Shahidi and Ambigaipalan, 2015; Zhong and 5. Outlook Shahidi, 2012). Surely, several works on bioavailability and physiological ac- Natural phenolic consumption has been acknowledged as an indis- tivity of the prevalent natural or synthetic phenolic standards/mix- pensable factor of a healthy diet. Apart from their well-recognized tures have been carried out but due to the diversity of phenolics antioxidant activity, other potential health effects of phenolics and the personal variation, there is still a need for a more clear such as anti-inflammatory, anti-cancer, antimutagenic, cardio-/ and thorough understanding of the specific patterns of phenolic hepato-/neuroprotective, antihypertensive, anti-diabetic, and diu- bioavailability. Moreover, there are no recommended dietary ref- retic effects, as well as inhibition of viral multiplication, blood erence intake (DRI) levels for polyphenolics as no exact physi- coagulation, histamine release, and cyclooxygenases activity have ological evidence exists to verify their nutritional and healthful

Table 18. Flavonoid standards catabolism rate by pig caecal microflora

Substrate concentration in Percentage (%) remained after incubation, h Substrate diluted pig caecal inoculum, mM 2 4 6 8 10 24 Galangin 125 95.8 ± 8.8 83.3 ± 5.9 54.2 ± 5.8 19.8 ± 4.4 7.3 ± 1.5 0 Kaempferol 125 55.5 ± 13.7 33.3 ± 5.9 5.6 ± 0.9 0 0 0 Apigenin 175 94.4 ± 1.9 91.0 ± 4.9 78.5 ± 6.9 78.4 ± 1.0 67.4 ± 1.0 59.0 ± 0.9 Luteolin 175 95.8 ± 1.9 81.6 ± 1.9 86.1 ± 3.9 82.6 ± 4.9 65.3 ± 7.9 56.2 ± 4.9 Quercetin 125 53.7 ± 1.5 38.9 ± 1.5 18.9 ± 3.0 5.3 ± 1.5 0 0 Chrysin 175 100.0 ± 3.9 99.9 ± 6.0 98.6 ± 9.9 100.7 ± 1.0 98.6 ± 4.0 99.9 ± 5.9

Adapted from Labib et al. (2006).

Journal of Food Bioactives | www.isnff-jfb.com 59 Bioaccessibility and bioavailability of phenolic compounds Shahidi et al. qualification, so phenolic supplements cannot even legally be trition. Cochrane Database Syst Rev. (6). labeled with either antioxidant capacity or any other nutritional/ Astorga, B., Ekins, S., Morales, M., and Wright, S.H. (2012). Molecular de- functional claims in the US and many other countries. As well, terminants of ligand selectivity for the human multidrug and toxin standardization and legislation of phenolic-rich herbal and phar- extruder proteins MATE1 and MATE2-K. J. Pharmacol. Exp. Ther. maceutical products are also lacking consensus and compatibility 341(3): 743–755. Aura, A.-M. (2008). Microbial metabolism of dietary phenolic compounds in different regions/countries such as EU, US, Japan, South Ko- in the colon. Phytochem. Rev. 7(3): 407–429. rea, and China. Various natural/artificial phenolic nutraceutical, Aura, A.-M., Martin-Lopez, P., O’Leary, K.A., Williamson, G., Oksman-Cal- pharmaceutical and food additive products are expected to be ver- dentey, K.-M., Poutanen, K., and Santos-Buelga, C. (2005). In vitro ified, applied and approved. More efforts are also in progress, thus metabolism of anthocyanins by human gut microflora. Eur. J. Nutr. a number of bioavailability studies covering phenolic digestion, 44(3): 133–142. absorption, transport, metabolism, colonic catabolism, excretion, Aura, A.-M., O’leary, K., Williamson, G., Ojala, M., Bailey, M., Puupponen- and physiological effects are still in need of further clarification Pimiä, R., Nuutila, A., Oksman-Caldentey, K.-M., and Poutanen, K. and elaboration. (2002). Quercetin derivatives are deconjugated and converted to -hy droxyphenylacetic acids but not methylated by human fecal flora in vitro. J. Agric. Food Chem. 50(6): 1725–1730. 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